AU2017289021A1 - Novel pyrazole derivative as ALK5 inhibitor and uses thereof - Google Patents

Novel pyrazole derivative as ALK5 inhibitor and uses thereof Download PDF

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AU2017289021A1
AU2017289021A1 AU2017289021A AU2017289021A AU2017289021A1 AU 2017289021 A1 AU2017289021 A1 AU 2017289021A1 AU 2017289021 A AU2017289021 A AU 2017289021A AU 2017289021 A AU2017289021 A AU 2017289021A AU 2017289021 A1 AU2017289021 A1 AU 2017289021A1
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methylpyridin
carboxyamide
pyrazole
benzo
phenyl
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Seung Ah JUN
Young Hee Jung
Kyung Ik Lee
Ji Young Song
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Hanmi Pharmaceutical Co Ltd
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Hanmi Pharmaceutical Co Ltd
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Abstract

The present invention relates to a novel substituted pyrazole derivative, having the effect of inhibiting the serine/threonine kinase activity, targeting the receptor ALK5 of TGF-β. A pharmaceutical composition containing a compound of the present invention as an active ingredient can be usefully used in the treatment and/or prevention of cancer, an autoimmune disease, a fibrotic disease, an inflammatory disease, a neurodegenerative disease, an infectious disease, a pulmonary disease, a cardiovascular disease or a metabolic disease or other diseases associated with a decrease in TGF family signaling activity.

Description

[DESCRIPTION] [Disclosure Title]
NOVEL PYRAZOLE DERIVATIVES AS ALK5 INHIBITORS AND USE THEREOF [Technical Field] [0001] The present disclosure relates to a novel pyrazole derivative compound and use thereof, and in particular, to a novel pyrazole derivative having an ALK5 activity inhibiting effect, a pharmaceutically acceptable salt or solvate thereof, a pharmaceutical composition including such a compound as an active ingredient, and use thereof.
[Background Art] [0002] A transforming growth factor-β (TGF-β) signal regulates a developmental stage and cell activity in various ways, and thereby regulates various cell responses such as cell proliferation, differentiation, cell migration and cell death. TGF-β has at least 3 isoforms called TGF-βΙ, ΤΟΡ-β2 and TGF^3, and TGF-βΙ may be divided into two wellpreserved single membrane serine/threonine kinase type I (ALK5) and formulation TGFβ receptor. When oligomerization is induced by a ligand, the formulation receptor induces activation of ALK5 by hyperphosphorylating serine/threonine residues of ALK5 and producing Smad protein bonding sites. Activated ALK5 phosphorylates Smad2 and Smad3 to form a complex with Smad4, and migrates into the nucleus to regulate gene expression (Pennison, M. Pasche, B., Curr Opin Oncol (2007) 19, 579-85, Attisano, L., Wrana, JL. Science (2002) 296, 1646-47). Accordingly, abnormality in the TGF-β signaling function causes a number of human diseases (for example, deposition of extracellular matrix, inflammatory response, fibrotic dysfunction and advanced cancer).
[0003] Meanwhile, TGF-β responds to cancer formation in an early stage of cancer, and facilitates metastasis formation in cancer growing and late tumor stages. For cancer cells, TGF-β facilitates proliferation, epithelial mesenchymal transition (EMT), penetration and metastasis, acts as a major regulator of autocrine and paracrine between a cancer and microenvironments around the cancer, and acts on changes in the microenvironment, neovascularization and immunosuppression, which is effective in inhibiting tumor proliferation and cancer metastasis. An important role played by TGFβ in facilitating cancer growth also indicates a correlation between potent TGF-β expression and poor prognosis.
[0004] In addition, fibrosis of organs and tissues is considered to be well-known as a relation between the TGF-β and diseases. EMT activity has been known to be a main mechanism causing fibrosis to date. An inhibitor of intercellular signaling pathways is a useful therapeutic for fibroplasia. It is known to be centrally related to fibrosis of organs such as kidney, liver, lung, heart, bone marrow and skin. From such a point, it has become clear that inhibiting TGF-β is useful for preventing and treating all diseases accompanying fibrosis including chronic renal disease.
[0005] A compound according to the present disclosure and a salt thereof have been found to have very important pharmacological properties while being highly tolerant. Particularly, these exhibit TGF-β receptor I kinase (ALK5)-inhibiting properties. Accordingly, for signaling pathway ingredients of the TGF-β family, development of inhibitors in treating or preventing diseases associated with an abnormal behavior of this signaling pathway has been required.
[Disclosure] [Technical Problem] [0006] The present disclosure is directed to providing a compound capable of selectively and effectively inhibiting ALK5 and/or ALK4, or a pharmaceutically acceptable salt thereof.
[0007] The present disclosure is also directed to providing a pharmaceutical composition including the compound as an active ingredient.
[0008] The present disclosure is also directed to providing a pharmaceutical composition capable of, by including the compound as an active ingredient, selectively and effectively inhibiting ALK5 and/or ALK4 and thereby preventing or treating various diseases mediated thereby.
[Technical Solution] [0009] In view of the above, one embodiment of the present disclosure provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
[0010] [Chemical Formula 1] [0011]
Figure AU2017289021A1_D0001
(R3)m [0012] in Chemical Formula 1, [0013] X is N or CH;
[0014] a ring A is C3-6 cycloalkylene, Ce-io arylene, C5-10 heteroarylene containing to 4 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S;
[0015] Ris are each independently hydrogen, halogen, or linear or branched C1-6 alkyl, or halo C1-6 alkyl, and when there are a plurality of Ris, these are the same as or different from each other;
Λι 9 Λΐ1' V
[0016] N-J R2S are each independently
I
Figure AU2017289021A1_D0002
Figure AU2017289021A1_D0003
[0017] R3 is hydrogen, halogen, linear or branched C1-6 alkyl, linear or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl unsubstituted or substituted with R4, C6-10 heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, (CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)aNR4R5, -(CH2)a-NO2, -(CH2)a-CN, -(CH2)a-COR4, -(CH2)a-CO2R4, -(CH2)a-CONR4R5, (CH2)a-NHCOR4, -(CH2)a-SR4, -(CH2)a-NHSO2R4, -(CH2)aSOR6, -(CH2)a-SO2R6, 10 (CH2)a-SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4R5, or when there are a plurality of R3S and they are adjacent to each other, they may be linked to each other to form a 5membered or 6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms may be included in the ring, and the heteroatoms may be further oxidized;
[0018] R4 and R5 are each independently hydrogen, linear or branched C1-6 alkyl, linear or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkenyl, C1-6 carbonyl, C6-12 aryl, -(Cthjb-NReR?, or saturated or partially unsaturated 5-membered to 10-membered monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S;
[0019] Re and R7 are each independently hydrogen, hydroxy, C1-6 alkyl, halo C1-6 alkyl or C3-6 cycloalkyl;
[0020] a and b are an integer of 0 to 4; and [0021] 1, m and n are each independently an integer of 0 to 4.
[0022] Another embodiment of the present disclosure provides a preventive or therapeutic use for diseases mediated by an ALK5 and/or ALK4 receptor in a pharmaceutical composition including the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
[0023] The disease is particularly preferably selected from the group consisting of fibrotic diseases (for example, scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical trauma, spinal trauma, CNS injury, acute lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic renal disorder, hypertension-induced renal disorder, liver or biliary fibrosis, liver cirrhosis, primary biliary sclerosis, fatty liver disease, primary sclerogenous cholangitis, recurrent stenosis, cardiac fibrosis, ocular damage, fibrosclerosis, fibrous cancer, fibromyoma, fibroma, fibroadenoma, fibrosarcoma, grafted arterial disorder, and keloid); dehydration of nerve multiple sclerosis; Alzheimer’s disease; great sinus vasculophathy; and tumor cells (for example, squamous cell carcinoma, multiple myeloma, melanoma, glioma, glioblastoma, leukemia, and carcinomas of lung, breast, ovary, cervix, liver, biliary duct, gastrointestinal tract, pancreas, prostate, and head and neck).
[Advantageous Effects] [0024] A novel pyrazole derivative according to the present disclosure is capable of selectively or simultaneously inhibiting various diseases mediated by TGF-β, particularly ALK5 and/or ALK4. Accordingly, the novel derivative according to the present invention is useful in treating or preventing fibrotic diseases (for example, scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical trauma, spinal trauma, CNS injury, acute lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic renal disorder, hypertensioninduced renal disorder, liver or biliary fibrosis, liver cirrhosis, primary biliary sclerosis, fatty liver disease, primary sclerogenous cholangitis, recurrent stenosis, cardiac fibrosis, ocular damage, fibrosclerosis, fibrous cancer, fibromyoma, fibroma, fibroadenoma, fibrosarcoma, grafted arterial disorder, and keloid); dehydration of nerve multiple sclerosis; Alzheimer’s disease; great sinus vasculophathy; and tumor cells (for example, squamous cell carcinoma, multiple myeloma, melanoma, glioma, glioblastoma, leukemia, and carcinomas of lung, breast, ovary, cervix, liver, biliary duck, gastrointestinal tract, pancreas, prostate, and head and neck).
[Mode for Disclosure] [0025] Definitions listed below are definitions of various terms used for describing the present disclosure. These definitions are used throughout the specification individually or as a part of terms including these unless limited otherwise.
[0026] The term ‘halogen’ used in the present specification means, unless mentioned otherwise, any one of fluorine, chlorine, bromine, iodine, or all of these.
[0027] The term ‘alkyl’ used in the present specification refers to, unless mentioned otherwise, a saturated linear or branched hydrocarbon radical expressed by CnH2n+i, and specifically, refers to a saturated linear or branched hydrocarbon radical each including carbon atoms between 1 to 6, 1 to 8, 1 to 10, or 1 to 20. Examples of these radicals include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals, but are not limited thereto.
[0028] The term ‘alkenyl’ used in the present specification refers to, unless mentioned otherwise, a monovalent group derived from an unsaturated linear or branched hydrocarbon moiety having at least one carbon-carbon double bond, and specifically, refers to an unsaturated linear or branched monovalent group each including carbon atoms between 2 to 6, 2 to 8, 2 to 10, or 2 to 20. Examples thereof include ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl and octenyl radicals, but are not limited thereto. [0029] The term ‘cycloalkyl’ used in the present specification refers to, unless mentioned otherwise, a monovalent group derived from a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring compound. For example, examples of C3-C8-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclo hexyl, cyclopentyl and cyclooctyl; and examples of C3-C12-cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo[2.2.2]octyl. A monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond obtained by removing a single hydrogen atom is also considered. Examples of such a group include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, cyclooctenyl and the like.
[0030] The term ‘cycloalkenyl’ used in the present specification refers to, unless mentioned otherwise, a partially unsaturated carbocyclic ring containing 3 to 6 carbon atoms and having a carbon-carbon double bond in the ring. Examples of such a group include, but are not limited to, cyclopentenyl, cyclohexenyl and the like.
[0031] The term ‘aryl’ used in the present specification refers to, unless mentioned otherwise, a mono- or poly-cyclic carbocyclic ring system having fused or non-fused one or more aromatic rings, and although not limited thereto, includes phenyl, naphthyl, tetrahydronaphthyl, indenyl, idenyl and the like.
[0032] The term ‘heterocycloalkyl’ used in the present specification refers to, unless mentioned otherwise, a saturated or partially unsaturated 3-membered to 10membered monocyclic or polycyclic substituent containing one or more, for example, 1 to 4 heteroatoms selected from among N, O and S. Examples of the monocyclic heterocycloalkyl may include piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and groups similar thereto, but are not limited thereto.
[0033] The term ‘heteroaryl’ used in the present specification means, unless mentioned otherwise, a 5-membered to 12-membered monocyclic, or bicyclic or higher aromatic group containing one or more, for example, 1 to 4 heteroatoms selected from among Ο, N and S. Examples of the monocyclic heteroaryl may include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and groups similar thereto, but are not limited thereto. Examples of the bicyclic heteroaryl may include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl and groups similar thereto, but are not limited thereto. [0034] The term ‘non-aromatic fused heteropolycyclic ring’ used in the present specification means a group having two or more rings fused to each other, including a heteroatom selected from among N, O and S as a ring-forming atom other than carbon, and having the whole molecule exhibiting non-aromacity (for example, having 5 to 10 nuclear atoms). Examples of the non-aromatic fused heteropolycyclic ring may include benzo[d][l,3]dioxol and the like, but are not limited thereto.
[0035]
Hereinafter, the present disclosure will be described in more detail.
[0036] One embodiment of the present disclosure provides a compound of the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
[0037] [Chemical Formula 1] [0038]
Figure AU2017289021A1_D0004
(Rjlm [0039] in Chemical Formula 1, [0040] X is N or CH;
[0041] a ring A is C3-6 cycloalkylene, Ce-io arylene, C5-10 heteroarylene containing to 4 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S;
[0042] Ris are each independently hydrogen, halogen, or linear or branched C1-6 alkyl, or halo C1-6 alkyl, and when there are a plurality of Ris, these are the same as or different from each other;
Figure AU2017289021A1_D0005
[0043]
R2S are each independently
Figure AU2017289021A1_D0006
Figure AU2017289021A1_D0007
[0044] R3 is hydrogen, halogen, linear or branched C1-6 alkyl, linear or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl unsubstituted or substituted with
R4, C6-10 heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, (CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)aNR4R5, -(CH2)a-NO2, -(CH2)a-CN, -(CH2)a-COR4, -(CH2)a-CO2R4, -(CH2)a-CONR4R5, (CH2)a-NHCOR4, -(CH2)a-SR4, -(CH2)a-NHSO2R4, -(CH2)aSOR6, -(CH2)a-SO2R6, 10 (CH2)a-SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4R5, or when there are a plurality of R3S and they are adjacent to each other, they may be linked to each other to form a 5membered or 6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms may be included in the ring, and the heteroatoms may be further oxidized;
[0045] R4 and R5 are each independently hydrogen, linear or branched C1-6 alkyl, linear or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkenyl, C1-6 carbonyl, C6-12 aryl, -(Cthjb-NReR?, or saturated or partially unsaturated 5-membered to 10-membered monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S;
[0046] Re and R7 are each independently hydrogen, hydroxy, C1-6 alkyl, halo C1-6 alkyl or C3-6 cycloalkyl;
[0047] a and b are an integer of 0 to 4; and [0048] 1, m and n are each independently an integer of 0 to 4.
[0049] In one specific embodiment of the present disclosure, X may be N, and Ri may be C1-6 alkyl.
[0050] In one specific embodiment of the present disclosure, the ring A may be phenyl, pyrazole, pyridinyl or benzo[d][l,3]dioxol.
[0051] In one specific embodiment of the present disclosure, the compound of
Chemical Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto:
[0052] (1) 5-(benzo[<i]thiazol-6-yl)-A-(4-methoxyphenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0053] (2) 5-(benzo[<i]thiazol-6-yl)-A-(4-ethoxyphenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0054] (3) 5-(benzo[<i]thiazol-6-yl)-A-(4-(cyclopropylmethoxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[0055] (4) 5-(benzo[<i]thiazol-6-yl)-A-(4-(2-methoxyethoxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[0056] (5) 5-(benzo[<i]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-A-(4(trifluoromethoxy)phenyl)-l//-pyrazole-3-carboxyamide;
[0057] (6) 5-(benzo[<i]thiazol-6-yl)-A-(4-(benzyloxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[0058] (7) 2V-(benzo[<7] [l,3]dioxo 1-5-yl)-5-(benzo[<7] thiazo 1-6-yl)-1-(6methy lp yridin- 2- yI)-1 -77- p yrazo le- 3 -carboxy amide;
[0059] (8) 5-(benzo[<7]thiazol-6-yl)-2V-(4-fluoro-3-methoxyphenyl)-1-(6methy lp yridin- 2- yI)-177- p yrazo le- 3 -carboxy amide;
[0060] (9) 5-(benzo[<7]thiazol-6-yl)-2V-(2-fluoro-4-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0061] (10) 5-(benzo[<7]thiazol-6-yl)-2V-(3-fluoro-4-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0062] (11) 5-(benzo[<7]thiazol-6-yl)-2V-(3-aminophenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0063] (12) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(methylamino)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0064] (13) 5 -(benzo | <71 thiazo 1- 6- yl) -N- (4- (dimethylamino )pheny 1) -1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0065] (14) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-nitrophenyl)177-p yrazo le-3-carboxy amide;
[0066] (15) 5-(benzo[<7]thiazol-6-yl)-2V-(4-((2(dimethylamino)ethyl)(methyl)amino) phenyl)-l-(6-methylpyridin-2-yl)-177-p yrazo le-3carboxyamide;
[0067] (16) 5- (benzo | <71 thiazo 1- 6- yl) -N- (4- (3 -(dimethylamino )p yrro lidin-1 yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[0068] (17) 5-(benzo[<7]thiazol-6-yl)-2V-(3-chloro-4-(octahydro-677-pyrrolo[3,4£]pyridin-6-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[0069] (18) 5 - (benzo [<7] thiazol- 6- y 1) -1 - (6- methyip yridin- 2- yl) -N- phe n y 1-1Hpyrazole-3-carboxyamide;
[0070] (19) 5-(benzo[<7]thiazol-6-yl)-A^-(3-tolyl)-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
[0071] (20) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3viny lpheny 1) -177-p yrazo le- 3 -carboxy amide;
[0072] (21) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(trifluoromethyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0073] (22) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(cyanophenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0074] (23) 5-(benzo[<7]thiazol-6-yl)-2V-(3-acetylphenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0075] (24) ethyl 3-(5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-177p yrazo le- 3 -carboxy amido )benzo ate;
[0076] (25) 5-(benzo[<i]thiazol-6-yl)-iV-(4-(methylcarbamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0077] (26) 5-(benzo[<7]thiazol-6-yl)-2V-(4-acetamidophenyl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxyamide;
[0078] (27) 5-(benzo[<7]thiazol-6-yl)-2V-(2-fluorophenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0079] (28) 5-(benzo[<7]thiazol-6-yl)-2V-(3-fluorophenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0080] (29) 5-(benzo[<7]thiazol-6-yl)-2V-(4-fluorophenyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[0081] (30) 5-(benzo[<7]thiazol-6-yl)-2V-(3,4-difluorophenyl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxyamide;
[0082] (31) 5-(benzo[<7]thiazol-6-yl)-A^-(2-chlorophenyl)- l-(6-methylpyridin-2yl)- 177-pyrazole-3-carboxyamide;
[0083] (32) 5-(benzo[<7]thiazol-6-yl)-2V-(3-chlorophenyl)- l-(6-methylpyridin-2yl)-1 A/-pyrazole-3-carboxyarnide;
[0084] (33) 5-(benzo[<7]thiazol-6-yl)-2V-(4-chlorophenyl)- l-(6-methylpyridin-2yl)-1 /¥-pyrazole-3-carboxyamide;
[0085] (34) 5-(benzo[<7]thiazol-6-yl)-2V-(4-bromophenyl)- l-(6-methylpyridin-2yl)-1 /¥-pyrazole-3-carboxyamide;
[0086] (35) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(methylthio)phenyl)-177-pyrazole-3-carboxyamide;
[0087] (36) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4(methylthio)phenyl)-177-pyrazole-3-carboxyamide;
[0088] (37) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(cyclopropylthio)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[0089] (38) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(methylsulfinyl)phenyl)-177-pyrazole-3-carboxyamide;
[0090] (39) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4(methylsulfinyl)phenyl)-177-pyrazole-3-carboxyamide;
[0091] (40) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(methylsulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
[0092] (41) 5- (benzo | <71 thiazo 1- 6- yl) -1 - (6- methyip yridin- 2- y 1) -N- (4(methylsulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
[0093] (42) 5-(benzo[<7] thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(4(propylsulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
[0094] (43) 5-(benzo[<7]thiazol-6-yl)-A^-(4-(cyclopropylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[0095] (44) 5-(benzo[<7]thiazol-6-yl)-2V-(2-fluoro-4-(methylsulfonyl)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[0096] (45) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3sulfamoylphenyl)-177-pyrazole-3-carboxyamide;
[0097] (46) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4sulfamoylphenyl)-177-pyrazole-3-carboxyamide;
[0098] (47) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3-(iVmethylsulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
[0099] (48) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-(iVmethylsulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
[00100] (49) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(2V-cyclopropylsulfamoyl)phenyl)-1(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00101] (50) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(2V-cyclopropylsulfamoyl)phenyl)-1(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00102] (51) 5-(benzo[<7]thiazol-6-yl)-iV-(3-(iV,iV-dimethylsulfamoyl)phenyl)-1-(6methyip yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00103] (52) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(2V,2V-dimethylsulfamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00104] (53) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(methylsulfonamido)phenyl)-177-pyrazole-3-carboxyamide;
[00105] (54) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(cyclopropanesulfonamido)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00106] (55) 5-(benzo[<7]thiazol-6-yl)-A^-(4-(cyclopropanesulfonamido)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00107] (56) 4-(5-(benzo[<7]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)- 177-pyrazole-3carboxyamido)benzenesulfonic acid;
[00108] (57) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4((trifluoromethyl)sulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
[00109] (58) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-(iV-(2,2,2trifluoroethyl)sulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
[00110] (59) 5-(benzo[<7]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4((methylsulfonyl)methyl)phenyl)-177-pyrazole-3-carboxyamide;
[00111] (60) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(sulfamoylmethyl)phenyl)-177-pyrazole-3-carboxyamide;
[00112] (61) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4(sulfamoylmethyl)phenyl)-177-pyrazole-3-carboxyamide;
[00113] (62) 5-(benzo[<7]thiazol-6-yl)-A^-(4-fluoro-3-(sulfamoylmethyl)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00114] (63) 5-(benzo[<7]thiazol-6-yl)-2V-(4-((l,l-dioxidotetrahydrothiophen-3yl)amino)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00115] (64) 5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-2V-(pyridin-4-yl)177-p yr azo le-3-carboxy amide;
[00116] (65) 5-(benzo[<7]thiazol-6-yl)-2V-(6-methoxypyridin-3-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00117] (66) 5-(benzo[<7]thiazol-6-yl)-2V-(2-methoxypyridin-4-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00118] (67) 5-(benzo[<7]thiazol-6-yl)-A^-(6-(methylthio)pyridin-3-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00119] (68) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(6(methylsulfonyl)pyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00120] (69) 5-(benzo[<7]thiazol-6-yl)-7V-(6-(methylsulfonyl)pyridin-3-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00121] (70) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(2(methylsulfonyl)pyridin-4-yl)-177-pyrazole-3-carboxyamide;
[00122] (71) 5-(benzo[<7]thiazol-6-yl)-A^-(6-fluoropyridin-3-yl)-1-(6methylpyridin-2- yI)-1 /7- pyrazole-3-carboxyamide;
[00123] (72) 5-(benzo[<7|thiazol-6-yl)-7V-(2-fluoropyridin-4-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00124] (73) 5-(benzo[<7]thiazol-6-yl)-7V-(6-chloropyridin-3-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00125] (74) 5-(benzo[<7]thiazol-6-yl)-7V-(2-chloropyridin-4-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00126] (75) 5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(thiazo 1-2-yl)177-p yrazo le-3-carboxy amide;
[00127] (76) 5-(benzo[<7]thiazol-6-yl)-7V-benzyl- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
[00128] (77) 5-(benzo[<7]thiazol-6-yl)-7V-(2-fluorobenzyl)- l-(6-methylpyridin-2yl)- 177-pyrazole-3-carboxyamide;
[00129] (78) 5-(benzo[<7]thiazol-6-yl)-7V-(3-fluorobenzyl)- l-(6-methylpyridin-2yl)- 177-pyrazole-3-carboxyamide;
[00130] (79) 5-(benzo[<7]thiazol-6-yl)-A^-(4-fluorobenzyl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[00131] (80) 5-(benzo[d]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-7V-(l(methylsulfonyl)- 177-pyrazol-4-yl)-177-pyrazole-3-carboxyamide;
[00132] (81) 5-(benzo[d]thiazo l-6-yl)-2V-(l-(cyclopropylsulfonyl)-177-pyrazo 1-4yl)- l-(6-methylpyridin-2-yl)- 177-pyrazole-3-carboxyamide;
[00133] (82) 5-(benzo[<7]thiazol-6-yl)-2V-(3-hydroxyphenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[00134] (83) 5-(benzo[<7]thiazol-6-yl)-2V-(4-hydroxyphenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[00135] (84) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(hydroxymethyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00136] (85) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(hydroxymethyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00137] (86) 2V-(4-aminophenyl)-5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[00138] (87) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(butylamino)phenyl)-1-(6methylpyridin-2- yI)-1 /7- pyrazole-3-carboxyamide;
[00139] (88) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(cyclopropylamino)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00140] (89) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-A^-(4-(5'methylsulfonimidoyl)phenyl)-177-pyrazole-3-carboxyamide;
[00141] (90) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00142] (91) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(3-methoxyphenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00143] (92) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00144] (93) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-hydroxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00145] (94) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-isopropylphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00146] (95) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(2methoxyethoxy)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00147] (96) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(benzo[d][l,3]dioxol-5-yl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00148] (97) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(2-fluoro-4-methoxyphenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00149] (98) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(3-fluoro-4-methoxyphenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00150] (99) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(2(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
[00151] (100) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-7V(3-(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
[00152] (101) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(4-(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
[00153] (102) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(3(dimethylamino)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00154] (103) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-A^-(4-aminophenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00155] (104) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4(dimethylamino)phenyl)-l-(6-methylpyridin-2-yl)-l-77-pyrazole-3-carboxyamide;
[00156] (105) 5-([ 1,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(pyrro lidin-1yl)phenyl) l-(6-methylpyridin-2-yl)-1 /¥-pyrazole-3-carboxyamide;
[00157] (106) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-((2-(dimethylamino) ethyl)(methyl)amino)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00158] (107) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-(4-methylpiperazin-lyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00159] (108) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-(4-acetylpiperazin-lyl)phenyl)-l-(6-methylpyridin-2-yl)-lH-pyrazole-3-carboxyamide;
[00160] (109) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-(( 1,1dioxido tetrahydro thiophen- 3 - yl) amino )pheny 1) -1 - (6- methyip yridin- 2- yl) -177-p yrazo le- 3 carboxyamide;
[00161] (HO) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-acetamidophenyl)-l-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00162] (111) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-7V-(4((dimethy lamino) methyl)pheny 1) -1 - (6-methy lp yridin- 2- yl) -177-p yrazo le- 3 carboxyamide;
[00163] (112) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(2(methylcarbamoyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00164] (113) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4(methylcarbamoyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00165] (114) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iVpheny 1-1 H-p yrazo le- 3 -carboxy amide;
[00166] (115) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(o-tolyl)-177-pyrazole-3-carboxyamide;
[00167] (116) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(m-tolyl)-177-pyrazole-3-carboxyamide;
[00168] (117) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(p-tolyl)-177-pyrazole-3-carboxyamide;
[00169] (118) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(3-(trifluoromethyl)phenyl)-177-pyrazole-3-carboxyamide;
[00170] (119) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV(4- viny lpheny 1) -177-p yrazo le- 3 -carboxy amide;
[00171] (120) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-cyanophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00172] (121) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-cyanophenyl)-1-(6methy lp yridin- 2- yl) -1 -77-p yrazo le- 3 -carboxy amide;
[00173] (122) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-acetylphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00174] (123) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-acetylphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00175] (124) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(2-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00176] (125) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00177] (126) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00178] (127) 5-([ 1,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(2-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00179] (128) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00180] (129) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00181] (130) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00182] (131) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00183] (132) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00184] (133) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,3-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00185] (134) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,4-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00186] (135) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,5-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00187] (136) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3,4-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00188] (137) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3,5-difluorophenyl)-1-(6methylpyridin-2- yI)-1 /7- pyrazole-3-carboxyamide;
[00189] (138) 5-([l,2,4]triazolo[ 1,5-a]pyridin-6-yl)-2V-(3-chloro-2-fluorophenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00190] (139) 5-([ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl)-2V-(4-chloro-2-fluorophenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00191] (140) 5-([ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl)-2V-(3-chloro-4-fluorophenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00192] (141) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(3,4-dichlorophenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00193] (142) 5-([ 1,2,4]triazolo[ 1,5-a]pyridin-6-yl)-2V-(2-bromo-4-fluorophenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00194] (143) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(3-(methoxythio)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00195] (144) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(methoxythio)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00196] (145) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(3-(methylsulfmyl)phenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00197] (146) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-(methylsulfmyl)phenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00198] (147) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4(methylsulfonyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00199] (148) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-sulfamoylphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00200] (149) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(Smethylsulfonimidoyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00201] (150) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(propylsulfonyl)phenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00202] (151) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(propylsulfonyl)phenyl)l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00203] (152) 5-([ 1,2,4]triazolo[l,5-a]pyridin-6-yl)-A^-(6-fluoropyridin-3-yl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00204] (153) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(6-chloropyridin-3-yl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00205] (154) 5-([l,2,4]triazolo[ 1,5-a]pyridin-6-yl)-2V-(6-methoxypyridin-3-yl)-1 (6-methylpyridin-2-yl)-1 //-pyrazole-3- carboxyamide;
[00206] (155) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00207] (156) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
[00208] (157) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00209] (158) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-methoxybenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00210] (159) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-methoxybenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00211] (160) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4(dimethylamino)benzyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00212] (161) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(-acetamidobenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00213] (162) 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-2V(l-(methylsulfonyl)-177-pyrazol-4-yl)-177-pyrazole-3-carboxyamide;
[00214] (163) 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-2V-(l-cyclopropyl sulfonyl)177-pyrazol-4-yl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00215] (164) 2V-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)- 177-pyrazole-3-carboxyamide;
[00216] (165) 2V-(3-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)- 177-pyrazole-3-carboxyamide;
[00217] (166) 2V-(2-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
[00218] (167) 2V-(4-(2-methoxyethoxy)phenyl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00219] (168) 2V-(benzo[<7][l,3]dioxol-5-yl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00220] (169) 2V-(2,3-dihydrobenzo[£][l,4]dioxin-6-yl)-l-(6-methylpyridin-2-yl)-
5-(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00221] (170) N- (4- (dimethylamino )pheny 1) -1 - (6- methyip yridin- 2- y 1) - 5 (quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00222] (171) l-(6-methylpyridin-2-yl)-iV-(4-morpholinophenyl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
[00223] (172) iV-(4-(4-methylpiperazin-l-yl)phenyl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00224] (173) iV-(4-(4-acetylpiperazin-l-yl)phenyl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00225] (174) iV-(4-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00226] (175) 2V-(3-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00227] (176) 2V-(2-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00228] (177) 1 - (6-methylp yridin- 2- y 1) -N- (4- (morpholino methy l)pheny 1) -5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00229] (178) iV-(4-acetylphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00230] (179) iV-(3-acetylphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00231] (180) l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-iV-(4(trifluoromethyl)phenyl)-177-pyrazole-3-carboxyamide;
[00232] (181) l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-iV-(3(trifluoromethyl)phenyl)-177-pyrazole-3-carboxyamide;
[00233] (18 2) N- (4- (methy lcarbamo y l)pheny 1) -1 - (6- methyip yridin- 2- y 1) - 5 (quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00234] (183) iV-(4-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00235] (184) iV-(3-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00236] (185) iV-(2-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00237] (186) A^-(3,4-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
[00238] (187) 2V-(2,4-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
[00239] (188) 2V-(2,3-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
[00240] (189) 2V-(4-chlorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00241] (190) 2V-(2-chlorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00242] (191) 2V-(4-bromophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00243] (192) 2V-(6-methoxypyridin-3-yl)-l-(6-niethylpyridin-2-yl)-5-(quinoxalin-
6-yl)-177-pyrazole-3-carboxyamide;
[00244] (193) 2V-(4-methoxybenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00245] (194) 2V-(4-cyanobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00246] (195) 2V-(3-acetylbenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00247] (196) 2V-(4-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00248] (197) 2V-(3-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00249] (198) 7V-(2-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)1 H-p yr azo le-3-carboxy amide;
[00250] (199) 2V-(4-chlorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)1 H-p yr azo le-3-carboxy amide;
[00251] (200) 2V-(3-chlorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)1 H-p yr azo le-3-carboxy amide;
[00252] (201) 2V-(2-chlorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)1 H-p yr azo le-3-carboxy amide;
[00253] (202) 7V-(2-fluorophenyl)-5-(quinoxalin-6-yl)-l-(m-tolyl)-177-pyrazole-3carboxyamide;
[00254] (203) l-(5-chloro-2-fluorophenyl)-2V-(4-methoxyphenyl)-5-(quinoxalin-6yl)-1 A/-pyrazole-3-carboxyamide;
[00255] (204) l-(5-chloro-2-fluorophenyl)-7V-(4-(dimethylamino)phenyl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00256] (205) 2V-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-1-(6trifluoromethyl)p yridin- 2- y 1) -1 H-p yr azo le- 3 -carboxy amide;
[00257] (206) Af-(4-(dimethylamino)phenyl)-5-(quinoxalin-6-yl)-1-(6trifluoromethyl)p yridin- 2- y 1) -1 H-p yr azo le- 3 -carboxy amide;
[00258] (207) l-(6-bromopyridin-2-yl)-7V-(4-methoxyphenyl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
[00259] (208) 1 - (6-bromop yridin- 2- yl) -N- (4- (dimethylamino )pheny 1) -5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
[00260] (209) 7V-(2-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-177pyrazole-3-carboxyamide;
[00261] (210) Af-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)1 H-p yr azo le-3-carboxy amide;
[00262] (211) l-(6-methylpyridin-2-yl)-2V-(4-(methylsulfonyl)phenyl)-5(quinolin-4-yl)-177-pyrazole-3-carboxyamide;
[00263] (212) 2V-(6-methoxypyridin-3-yl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4yl)-1 A/-pyrazole-3-carboxyamide;
[00264] (213) 2V-(6-chloropyridin-3-yl)- l-(6-methylpyridin-2-yl)-5-(quinolin-4yl)-1 A/-pyrazole-3-carboxyamide;
[00265] (214) 2V-(benzo[d][l,3]dioxo 1-5-yl)-l-(6-methylpyridin-2-yl)-5-(quinolin4-yl)-1 A/-pyrazole-3-carboxyamide;
[00266] (215) 2V-(3-fluoro-4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5(quinolin-4-yl)-177-pyrazole-3-carboxyamide;
[00267] (216) 2V-(2-fluoro-4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5(quinolin-4-yl)-177-pyrazole-3-carboxyamide;
[00268] (217) 2V-(4-(2-methoxyethoxy)phenyl)-l-(6-methylpyridin-2-yl)-5(quinolin-4-yl)-177-pyrazole-3-carboxyamide;
[00269] (218) 5-(benzo[c][l,2,5]oxadiazol-5-yl)-2V-(4(cyclopropylsulfonyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00270] (219) 5-(benzo[d]oxazol-6-yl)-2V-(2-fluorophenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
[00271] (220) 5-(benzo[d]oxazol-6-yl)-2V-(4-(cyclopropylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
[00272] (221) 2V-cyclopropyl-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol-4yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00273] (222) Af-(177-pyrazol-4-yl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol4-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00274] (223) 2V-(l-methyl-177-pyrazol-4-yl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)177-pyrazol-4-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00275] (224) A^-(l-(methylsulfonyl)-177-pyrazol-4-yl)-5-(4-fluoro-3-(l-(2hydroxy ethyl)- 177-pyrazol-4-yl)phenyl)- l-(6-methylpyridin-2-yl)- 177-pyrazole-3carboxyamide;
[00276] (225) 2V-(4-chlorophenyl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol4-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
[00277] (226) 2V-(4-(methylsulfonyl)phenyl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)177-pyrazol-4-yl)phenyl)-l-(6-methylpyridin-2-yl)- 177-pyrazole-3-carboxyamide; and [00278] (227) 2V-(2-fluorophenyl)-5-(thieno[3,2,c]pyridin-2-yl)-l-(m-tolyl)-177pyrazole-3-carboxyamide.
[00279] The compound of Chemical Formula 1 according to the present disclosure may be prepared using a method representatively illustrated in the following Reaction
Formula 1:
[00280] <Reaction Formula 1>
[00281] [00282]
Figure AU2017289021A1_D0008
Figure AU2017289021A1_D0009
NaOEt, EtOH
Figure AU2017289021A1_D0010
(Ri)l
Ax.
/ ' N UOH » N-N nH Η2Ν^Γ<Α;'(Ρ:!)η1
1,4-Dioxane, H2O D ,A/ «2 0 HATU, DIPEA, DMF
(2)
In Reaction Formula 1,
Figure AU2017289021A1_D0011
(1) [00283] Ri, R2, R3, A, 1, m and n each have the same definitions as in Chemical
Formula 1.
[00284] When describing the reaction in more detail with reference to Reaction
Formula 1, an acetyl compound having R2, diethyl oxalate and ethoxysodium solution are refluxed in an organic solvent (for example, ethanol) to obtain Compound (4). Compound (4) is refluxed with a hydrazinyl material having an (Ri)i group and the like to obtain Compound (3), and this may be stirred under 1,4-dioxane and lithium hydroxide to obtain Intermediate Compound (2). Next, Compound (2) may be reacted with an aniline derivative having an R3 group together with HATU and DIPEA in N, Wdimethylformamide to obtain a target compound of Chemical Formula 1 of the present disclosure.
[00285] The compound of Chemical Formula 1 according to the present disclosure may be prepared to a pharmaceutically acceptable salt form having an inorganic acid or an organic acid added thereto, and herein, examples of the preferred salts may include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or the like.
[00286] Specifically, the pharmaceutically acceptable salt according to the present disclosure may be prepared by dissolving the compound of Chemical Formula 1 in an organic solvent such as acetone, methanol, ethanol or acetonitrile, adding an organic acid or an inorganic acid thereto, and filtering crystals precipitated therefrom. Alternatively, the pharmaceutically acceptable salt may be prepared by vacuuming a solvent or excess acid in an acid-added reaction mixture to dry the residue, or prepared by filtering a salt precipitated from adding other organic solvents.
[00287] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may have a form of a hydrate or solvate, and such compounds are also included in the present disclosure.
[00288] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may effectively inhibit protein kinase. In one embodiment, the compound of the present disclosure may effectively prevent or treat diseases mediated by the ALK5 receptor or the ALK4 receptor, or both the ALK5 receptor and the ALK4 receptor. Specifically, the disease may be selected from the group consisting of kidney-, liver- or lung-fibrosis, glomerulonephritis, diabetic renal disease, erythematous nephritis, hypertension-induced renal disease, kidney interstitial fibrosis, kidney fibrosis derived from drug exposure complications, HIV-related renal disease, organ transplantation gangrene, liver fibrosis caused by all diseases, hepatic dysfunction caused by infection, alcohol-induced hepatitis, biliary disorder, pulmonary fibrosis, acute lung injury, adult respiratory pain syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis caused by infection or toxic factors, cardiac fibrosis after myocardial infarction, congestive heart failure, dilated cardiomyopathy, myocarditis, vascular stenosis, restenosis, atherosclerosis, visual impairment, corneal injury, proliferative vitreoretinopathy, excessive or exacerbated scar or keloid formation in the dermis occurring during wound healing from trauma or surgical wounds, peritoneum and subcutaneous adhesion, skin sclerosis, fibrosclerosis, progressive systemic sclerosis, dermatomyositis, multiple myositis, arthritis, osteoporosis, ulcer, impaired nerve function, male impotence, Alzheimer’s disease, Raynaud’s disease, fibrous cancer, metastasis growth of tumors, radiation-induced fibrosis and thrombosis, but is not limited thereto.
[00289] In one specific embodiment of the present disclosure, the compound of
Chemical Formula 1 or a pharmaceutically acceptable salt thereof may prevent or treat fibrotic diseases or fibrotic conditions. Herein, the fibrotic disease or the fibrotic condition may be selected from the group consisting of liver fibrosis, kidney fibrosis, pulmonary fibrosis, irritable pneumonia, interstitial fibrosis, systematic sclerodermie, macular degeneration, pancreas fibrosis, splenic fibrosis, cardiac fibrosis, species septic fibrosis, bone marrow fibrosis, vascular fibrosis, skin fibrosis, eye fibrosis, joint fibrosis, muscle fibrosis, thyroid fibrosis, endocardial myocardial fibrosis, peritoneal fibrosis, after peritoneal fibrosis, progressive congenital trophoblastic fibrosis, allogeneic systematic fibrosis, fibrotic complications of surgery and infection fibrosis, but is not limited thereto. [00290] In one specific embodiment of the present disclosure, the compound of
Chemical Formula 1 or a pharmaceutically acceptable salt thereof may effectively prevent or treat cancers or tumors, and may further effectively inhibit cancer cell metastasis as well. Herein, the cancer may be selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers, but is not limited thereto.
[00291] In one specific embodiment of the present disclosure, the compound of
Chemical Formula 1 or a pharmaceutically acceptable salt thereof may effectively prepvent or treat a carcinoma mediated by overexpression of TGFp. Herein, the carcinoma may be selected from the group consisting of carcinomas of lung, breast, liver, biliary, gastrointestinal tract, head and neck, pancreas, prostate and cervix, multiple myeloma, melanoma, glioma and glioblastoma, but is not limited thereto.
[00292] The compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof according to the present disclosure may strengthen therapeutic effects by being co-administered with other drugs for treating fibrotic diseases, cancers or tumors, inflammatory diseases, autoimmune diseases, proliferative diseases, hyperproliferative diseases or immunologically-mediated diseases.
[00293] Examples of the other drugs for treating cancers or tumors may include drugs such as cell signaling inhibitors (gleevec, iressa, tarceva and the like), mitotic inhibitors (vincristine, vinblastine and the like), alkylating agents (cyclophosphamide, thiotepa, busulfan and the like), anti-metabolites (tergaflor-based, methotrexate, gemcitabine and the like), topoisomerase inhibitors (irinotecan, topotecan, amsacrine, etoposide, teniposide and the like), immunotherapeutic agents (interferon α, β, γ, interleukin and the like) or anti-hormones (tamoxifen, leuprorelin, anastrozole and the like), but are not limited thereto, and one or more drugs selected from among these may be included in the pharmaceutical composition of the present disclosure.
[00294] Examples of the other drugs for treating inflammatory diseases, autoimmune diseases, proliferative diseases, hyperproliferative diseases or immunologically-mediated diseases may include drugs such as steroid drugs (prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone, dexamethasone and the like), methotrexate, leflunomide, anti-TNFa drugs (etanercept, infliximab, adalimumab and the like), calcineurin inhibitors (tacrolimus, pimecrolimus and the like) and antihistamine drugs (diphenhydramine, hydroxygene, loratadine, avastin, ketotifen, cetirizine, levocetirizine, fexofenadine and the like), but are not limited thereto, and one or more drugs selected from among these may be included in the pharmaceutical composition of the present disclosure.
[00295] The compound of Chemical Formula 1, a pharmaceutically acceptable salt thereof, or the like according to the present disclosure may be administered to a subject to prevent or treat the above-mentioned diseases. Herein, the dosage may vary depending on the subject to be treated, the severity of disease or condition, the rate of administration and the judgement of prescribing physician, however, the compound of Chemical Formula 1 may be commonly administered to a person as an active ingredient via an oral or parenteral route 1 to 4 times a day or on an on/off schedule with an amount of 0.1 mg to 2,000 mg and preferably 1 mg to 1,000 mg per day based on a body weight of 70 kg. In some cases, dosage less than the above-mentioned range may be more suited, and more dosage may be used without causing harmful side effects. More dosage may be dispensed in several smaller dosage over a day.
[00296] The pharmaceutical composition according to the present disclosure may be formulated using common methods, and may be prepared in various oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions or microemulsions, or parenteral administration forms such as intramuscular, intravenous or subcutaneous administration.
[00297] When the pharmaceutical composition according to the present disclosure is prepared in the form of oral formulation, examples of a carrier to be used may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, a surfactant, a suspension, an emulsifier, a diluent and the like. When the pharmaceutical composition according to the present disclosure is prepared in the form of an injection, water, a saline solution, an aqueous glucose solution, an aqueous pseudo-sugar solution, alcohol, glycol, ether (for example: polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, a surfactant, a suspension, an emulsifier and the like may be used as the carrier.
[00298] The compound of Chemical Formula 1 of the present disclosure may be
used in studies on kinases for biological and pathological phenomena, studies on intracellular signaling pathways mediated by kinases, and comparative evaluations on novel kinase inhibitors.
[00299] Hereinafter, the present disclosure will be described in detail with reference to examples. However, the following examples are for illustrative purposes only, and the present disclosure is not limited to the following examples.
[00300] <Reaction Formula 2>
0 0 0 -------------- 5-.p'Y''1’-------------- HStep 1 ' Step 2 Step 3 ° oh Ο ΓΊ1 /yVA'0''' ------“ N O-y - N OH W 0 Step 4 Step 5
[00301] Intermediate 1
[00302] [Preparation Example 1] 5-(Benzo[d]thiazol-6-yl)-l-(6-methylpyridin-
2-yl)- 1H-pyrazole-3-carboxylie acid
[00303] Step 1. Preparation of A-methoxy-A-methylbenzo[d]thiazole-6-
carboxyamide
[00304] After adding benzothiazole-6-carboxylic acid (5.0 g, 27.9 mmol), HATU
(15.9 g, 41.9 mmol) and DIPEA (11.7 mL, 83.7 mmol) to dichloromethane (87 mL) and A,A-dimethylformamide (22 mL), the result was stirred for 30 minutes. To the reaction solution, an N,O-dimethylhydroxylamine salt (3.0 g, 30.7 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered.
The filtrate was concentrated and purified using column chromatography to obtain a target compound (6.2 g).
[00305] Ή NMR spectrum (300 MHz, CDC13) δ 9.13(s, 1H), 8.36(d, 1H), 8.16(d, 1H), 7.87(dd, 1H), 3.57(s, 3H), 3.42(s, 3H).
[00306] Step 2, l-(Bcnzo|d|thiazol-6-yl)cthan- l-onc [00307] After dissolving A-methoxy-A-methylbenzo[d]thiazole-6-carboxyamide (6.2 g, 27.9 mmol) synthesized in Step 1 in anhydrous tetrahydrofuran (84 mL) under argon, 3 M methyl magnesium bromide (13.9 mL, 41.8 mmol) dissolved in diethyl ether was added dropwise thereto at 0°C. The reaction solution was warmed to room temperature and stirred for 12 hours. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (3.1 g).
[00308] Ή NMR spectrum (300 MHz, CDC13) δ 9.17(s, 1H), 8.62(s, 1H), 8.16(q,
2H), 2.71(s, 3H).
[00309] Step 3. Ethyl (Z)-4-(benzor<7]thiazol-6-yl)-4-hydroxy-2-oxo-3-butenoate [00310] After dissolving l-(benzo[<7]thiazol-6-yl)ethan-l-one (1.0 g, 5.6 mmol) synthesized in Step 2 and diethyl oxalate (1.5 mL, 11.3 mmol) in ethanol (2 mL), a 2 M ethoxysodium solution (5.6 mL, 11.3 mmol) was slowly added dropwise thereto at 50°C, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M HC1 dropwise thereto. Dichloro methane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (597 mg).
[00311] Ή NMR spectrum (300 MHz, CDC13) δ 9.19(s, 1H), 8.68(s, 1H), 8.20(q,
2H), 7.17(s, 1H), 4.43(q, 2H), 1.43(t, 3H).
[00312] Step 4, Ethyl 5-(bcnzok/|thiazol-6-yl)-l-(6-mcthylpyridin-2-yl)-1/7pyrazole-3-carboxylate [00313] After dissolving ethyl (Z)-4-(benzo[t/]thiazol-6-yl)-4-hydroxy-2-oxo-3butenoate (580 mg, 2.1 mmol) synthesized in Step 3 and 2-hydrazinyl-6-methylpyridine hydrochloric acid (350 mg, 2.2 mmol) in ethanol (10 mL), the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with saline and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (525 mg).
[00314] Ή NMR spectrum (300 MHz, CDC13) δ 9.04(s, 1H), 8.04(d, 1H), 7.97(d,
1H), 7.67(t, 1H), 7.41-7.33(m, 2H), 7.14-7.10(m, 2H), 7.47(q, 2H), 2.32(s, 3H), 1.43(t, 3H).
[00315] Step 5. 5-(Benzord]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-lH-pyrazole-3carboxylic acid [00316] After dissolving ethyl 5-(benzo[t/]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)177-pyrazole-3-carboxylate (520 mg, 1.4 mmol) synthesized in Step 4 in 1,4-dioxane (11 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70°C. After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid (hereto, inti then extracted by introducing chlorofoim/isoprOpano1) (3:1} thereto* The organic Sayer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated* The fill rale was purified using column chromatography to obtain
Intermediate 1 (394 mg).
[00317] JH NMR spectrum (300 MHz, CDClj) <5 9.34(s, 1H\ 8*O9(d. IH), 8.05(s.
1H), 7.75(1, 1H), 7 *44-7.3 9( m. 2H),7.2l(d* IH),7.13(s, IH), 2.36(s, 3H), [003181 < Read ion Formula 3>
Figure AU2017289021A1_D0012
Br
Step 1
Figure AU2017289021A1_D0013
O ? Ν^γ0Γ ______
Step 2
HC
Figure AU2017289021A1_D0014
O OH
Figure AU2017289021A1_D0015
Step 4
XX NH2HCI
H
Figure AU2017289021A1_D0016
Step 5
Figure AU2017289021A1_D0017
Intermediate 2 [00319] [00320] [Preparation Example 2] Preparation of 5-|[E2.4]triazi>lo[1.5 «Jpyridin-6-yl)-l-(ft-niethyipyridin-2-yl)-lF/-pyrazuk-3-carboxylic acid [003211 Step 1. Preparation of 2-hydraziny I-6-methyl pyridine hydrochloric acid salt [00322] A hydrazine hydrate (60 mL) was added to 2-bromo-6-methylpyridine (10.0 g, 58.1 mmol), and the result was healed under reflux for 4 hours. Alter terminating 15 lhe reaction* the result was extracted with ethyl acetate, and lhe obtained organic layer was vacuum concenlTaled, and acidified with 4 N-hydrochloric acid/dioxane (30 mL)* The produced solids were filtered* and the obtained solids were dried to oblain a target compound (9.3 g)* [00323] Ή NMR (300 MHz, DMSO-d6) δ 9.65 (brs, 3H), 7.60 (t, 1H), 6.75 (d, 1H),
6.69 (d, 1H), 2.41 (s, 3H).
[00324] MS (ESI+): m/z 124 [M+H]+ [00325] Step 2, Preparation of l-(| L2.4|triazolo| l.5-fz|pyridin-6-vl)cthan-l-onc [00326] After dissolving l-bromo-[l,2,4]triazolo[l,5-a]pyridine (1.1 g, 5.6 mmol) in ΛζΑ-dimethylformamide (15 mL) in a sealed tube, n-butyl vinyl ether (3.6 mL, 27.8 mmol), l,3-bis(diphenylphosphino)propane (161 mg, 0.4 mmol), palladium(II) acetate (37 mg, 0.2 mmol), potassium carbonate (922 mg, 6.7 mmol) and water (1.6 mL) were added thereto, and the result was heated under reflux for 16 hours. After lowering the temperature to room temperature, an aqueous 2 N-hydrochloric acid solution (10 mL) was added thereto, and the result was stirred for 30 minutes at room temperature. After terminating the reaction, the result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (410 mg).
[00327] Ή NMR (300 MHz, CDC13) δ 9.23 (s, 1H), 8.46 (s, 1H), 8.09 (d, 1H), 7.81 (d, 1H), 2.67 (s, 3H).
[00328] MS (ESI+): m/z 162 [M+H]+ [00329] Step 3. Preparation of (Z)-ethyl-4-([l,2,4]triazolo[l,5-a1pyridm-6-yr)-2hydroxy-4-oxo-2-butenoate [00330] After adding diethyl oxalate (1.3 mL, 9.9 mmol) to a 2 M ethoxysodium solution (5.0 mL, 9.9 mmol), a solution dissolving l-([l,2,4]triazolo[l,5-a]pyridin-6yl)ethan-l-one (400 mg, 2.5 mmol) synthesized in Step 1 in ethanol (3 mL) was added thereto, and the result was stirred for 2 hours at room temperature. The result was vacuum concentrated, and acidified by adding an aqueous 2 N hydrochloric acid solution dropwise thereto at 0°C. The result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and recrystallized with ether to obtain a target compound (444 mg).
[00331] Ή NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.69 (s, 1H), 8.16 (d, 1H), 7.95 (d, 1H), 7.30 (brs, 1H), 4.30 (q, 2H), 1.31 (t, 3H).
[00332] MS (ESI+): m/z 262 [M+H]+ [00333] Step 4, Preparation of ethyl-5-(ri,2,4]triazolo[l,5-<7|pyridin-6-yl)-l-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy late [00334] After dissolving (Z)-ethyl-4-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2hydroxy-4-oxo-2-butenoate (440 mg, 1.7 mmol) synthesized in Step 3 and the 2hydrazinyl-6-methylpyridine hydrochloric acid salt (268 mg, 1.7 mmol) synthesized in Step 1 in ethanol (6 mL), the result was stirred for 2 hours at 50°C. The result was vacuum concentrated, extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (446 mg).
[00335] Ή NMR (300 MHz, CDC13) δ 8.73 (s, 1H), 8.39 (s, 1H), 7.77-7.67 (m, 3H), 7.47 (d, 1H), 7.18-7.09 (m, 2H), 4.46 (q, 2H), 2.26 (s, 3H), 1.45 (t, 3H).
[00336] MS (ESI+): m/z 349 [M+H]+ [00337] Step 5. Preparation of 5-(ri,2,4]triazolo[l,5-<7|pyridin-6-yl)-l-(6methylp yridin-2-yl)-177-pyrazole-3-carboxylic acid [00338] After adding an aqueous 50% ethanol solution (5 mL) to ethyl-5([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxylate (440 mg, 1.3 mmol) synthesized in Step 4, the result was stirred for 1 hour at 50°C. The result was vacuum concentrated and acidified with an aqueous 2 N hydrochloric acid solution, and produced solids were filtered and dried to obtain Intermediate 2 (386 mg).
[00339] Ή NMR (300 MHz, DMSO-d6) δ 13.2 (brs, 1H), 9.15 (s, 1H), 8.52 (s, 1H),
7.91 (t, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.29 (d, 1H), 2.13 (s, 3H).
[00340] MS (ESI+): m/z 321 [M+H]+ [00341] <Reaction Formula 4>
[00342] [00343]
Figure AU2017289021A1_D0018
Figure AU2017289021A1_D0019
[Preparation Example 3]
Figure AU2017289021A1_D0020
Synthesis of l-(6-methylpyridin-2-yl)-5 (quinoxalin-6-yl)-lH-pyrazole-3-carboxylic acid [00344] Step 1. Preparation of l-(quinoxalin-6-yl)ethan-l-one [00345]
After adding 6-bromoquinoxaline (3.8 g, 18.2 mmol), n-butyl vinyl ether (12.3 mL,
95.2 mmol), potassium carbonate (3.1 g, 22.8 mmol),
1,3bis(diphenylphosphino)propane (504 mg, 1.3 mmol) and palladium(II) acetate (124 mg,
0.5 mmol) to A,A-dimethylformamide (47 mL) and water (6 mL), the result was stirred and refluxed for 6 hours. After terminating the reaction, the result was cooled to room temperature, 2 N hydrochloric acid was added thereto, and the result was stirred for 0.5 hours. Ethyl acetate was added thereto, the organic layer was washed with water and sodium bicarbonate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.4 g).
[00346] Ή NMR spectrum (300 MHz, DMSO-d6) δ 10.05(d, 1H), 9.73(t, 1H),
8.71(s, 1H), 7.97(d, 1H), 3.16(s, 3H).
[00347] Step 2, Preparation of ethyl (Z)-4-hydroxy-2-oxo-4-(quinoxalin-6-yl)-3butenoate [00348] After dissolving 6-(quinoxalin-6-yl)ethan-1-one (4.6 g, 27.0 mmol) synthesized in Step 1 and diethyl oxalate (7.3 mL, 53.9 mmol) in ethanol (9 mL), a 2 M ethoxysodium solution (26.9 mL, 53.9 mmol) was slowly added dropwise thereto at 50°C, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M HC1 dropwise thereto. Dichloro methane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (6.7 g).
[00349] Ή NMR spectrum (300 MHz, CDC13) δ 8.96(s, 2H), 8.78(s, 1H), 8.35(dd,
1H), 8.24(d, 1H), 7.27(s, 1H), 4.44(q, 2H), 1.45(t, 3H).
[00350] Step 3. Preparation of ethyl l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-pyrazole-3-carboxylate [00351] After dissolving (Z)-4-hydroxy-2-oxo-4-(quinoxalin-6-yl)-3-butenoate (2.7 g, 10.1 mmol) synthesized in Step 2 and 2-hydrazinyl-6-methylpyridine hydrochloric acid (1.3 g, 10.6 mmol) in ethanol, the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with sodium bicarbonate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.7 g).
(0Θ3521 Ή NMR spectrum (300 MHz, CDCh) <5 8.86(s, 2H), 8,()9(d, 1H >, 8.01 (d,
IHj, 7.73-7.62(m, 1H), 7.55(d, IH), 7.2O(s, IH), 7.13((1, 1H), 4.48(q, 2H), 2.24(s, 3H),
1.45(s. 3H).
[003531 Step 4. Preparatipri_of_ l·(6-methyl p^ridin_-2-y!)-5_-(tjuinoxaljn-6Σyί)7j Hpyrazole-3-carboxy lie acid [00354] After dissolving ethyl l-(6-melhylpyridin-2-yl)-5-(quinoxa]in-6-yl)-l/7pyrazole-3-carboxy late (2.6 g, 7.2 mmol) synthesized in Step 3 in 1,4-dioxane (40 mL). a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 3 hours at 7CPC. After terminating the reaction, the reaction solution was removed under vacuum, and water wras added thereto. Ethyl acetate was introduced thereto for extraction, the waler layer was acidified to a pH of 2 to 3. and the result was stirred for I hour at room temperature, Produced solids were filtered, washed with water, and dried to obtain Intermediate 3 (2.3 g).
[00355] JH MMR spectrum (300 MHz, DMSO-drd Λ 13.17(br, IH). 8.96( s, 2H),
8.06-7.92( m, 3H\ 7.72(dd. IH), 7.60(d, IH), 7.35-7.32(m, 2H), 2.15(s, 3H).
[00356] <Reaclion Formula 5>
[00357]
Figure AU2017289021A1_D0021
Figure AU2017289021A1_D0022
Figure AU2017289021A1_D0023
Step 3
Figure AU2017289021A1_D0024
[003581 [Preparation Example 4] l’(6-Methylpyridin-2-yl)-5-(quinolin-4-yl) lF/-pyrazole-3-carboxy lie acid [00359] S tep 1. Preparation of A/-methoxy-A-methylqui no line-4-c arboxyamide [00360] After adding quinoline-4-carboxylic acid (2.2 g, 12.8 mmol), HATU (5.8 g, 15.3 mmol) and DIPEA (6.7 mL, 38.4 mmol) to dichloromethane (25 mL), the result was stirred for 30 minutes. To the reaction solution, an N, O-dimethylhydroxylamine salt (1.9 g, 19.2 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (2.8 g).
[00361] Ή NMR spectrum (300 MHz, CDC13) δ 8.96(d, 1H), 8.15(d, 1H), 7.86(d, 1H), 7.76(t, 1H), 7.59(t, 1H), 7.39(d, 1H), 3.48-3.40(m, 6H).
[00362] Step 2, Preparation of l-(quinolin-4-yl)ethan-1-one [00363] After dissolving A-methoxy-A-methylquinoline-4-carboxyamide (2.8 g,
12.9 mmol) synthesized in Step 1 in anhydrous tetrahydrofuran (100 mL) under argon, 3 M methyl magnesium bromide (6.5 mL, 19.4 mmol) dissolved in diethyl ether was added dropwise thereto at 0°C. The reaction solution was warmed to room temperature, and stirred for 3 hours. 3M methyl magnesium bromide (3.0 mL, 9.0 mmol) dissolved in diethyl ether was further added dropwise thereto at 0°C. The reaction solution was warmed to room temperature and stirred for 12 hours. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (1.8 g).
[00364] Ή NMR spectrum (300 MHz, CDC13) δ 9.03(d, 1H), 8.46(d, 1H), 8.17(d,
1H), 7.77(t, 1H), 7.67-7.61(m, 2H), 2.75(s, 3H).
[00365]
Step 3. Preparation of ethyl (Z)-2-hydroxy-4-oxo-4-(quinolin-4-yl)but-2enoate [00366] After dissolving l-(quinolin-4-yl)ethan-1-one (1.0 g, 5.8 mmol) synthesized in Step 2 and diethyl oxalate (1.6 mL, 11.7 mmol) in ethanol (3 mL), a 2 M ethoxysodium solution (5.8 mL, 11.7 mmol) was slowly added dropwise thereto at 50°C, and the result was refluxed for 1 hour. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M hydrochloric acid drop wise thereto. Dichloro methane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then crystallized using a 1:1 mixed solution of hexane and ether to obtain a target compound (1.1 g).
[00367] Ή NMR spectrum (300 MHz, CDC13) δ 9.06(d, 1H), 8.40(d, 1H), 8.20(d, 1H), 7.8l(t, 1H), 7.70-7.63(m, 2H), 6.95(s, 1H), 4.42(q, 2H), 1.41(t, 3H).
[00368] Step 4, Preparation of ethyl l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)177-pyrazole-3-carboxylate [00369] After dissolving ethyl (Z)-2-hydroxy-4-oxo-4-(quinolin-4-yl)but-2-enoate (1.1 g, 4.2 mmol) synthesized in Step 3 and 2-hydrazinyl-6-methylpyridine hydrochloric acid (677 mg, 4.2 mmol) in ethanol (12 mL), the result was refluxed for 3 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with water and saline, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (1.1 g)· (00370] Ή NMR spectrum (300 MHz. CDCh) r) 8.92(d, IH). 8.13(d, IH), 7.707.56(m, 4H), 739(1, IH), 7.3lit, IH), 7,13(s, IH), 6.89( d, IH), 4.50(q, 2H), l.79(s, 3H).
1.46(1, 3H).
(00371] Step.^-5'_ I^epMat ion. of X-£6-j^thy1pyrid ίπ-Ξ^ν lj-54 quinqlin -4- y 1)-j H5 pyrazole-3-carboxy lie acid (003721 After dissolving ethyl l-(6-melhylpyridin-2-yl)-5-(quinolin-4-yl)-1/^pyrazole-3-carboxylate (1.1 g, 3.2 mmol) synthesized in Step 4 in 1,4-dioxane (J J mL), a
N lithium hydruxide solution (4.8 mL. 9.5 mmol) dissolved in water was introduced thereto, and the result was stirred for 2 hours al 45CC. AO er terminating the reaction, the reaction solution was removed under vacuum, and the result wras acidified to a pH of 2 to by adding 2 N hydrochloric acid thereto, and then stirred tor 1 hour at room temperature.
The result was vacuum filtered to obtain Intermediate 4 (960 mg).
(00373] JH NMR spectrum (300 MHz. DMSO-d^) J l3.O(bs, IH), 8.92(d. 1H),
8.07(d, IH), 7.81(1, IH), 7.71-7.6S(m, 2H), 7.50-7.44(m. 3H). 7.06(s, IH), 7.05(d. IH),
1.64(1,3H).
(003741 (00375] (00376] <Reaclion Formula 6>
0 nA/- Step 1 O — — ΓτΆ 1 Step 2 0 II N Λ.Χ
s»u Step 3
0 OH 0 -1' n H'- □ No7 A Intermediate 5
Step 4 Step 5
(Preparation Example 5] 5-f Benzo [c] [1,23 ] oxadiazol-5-y 1)-1-(6met by lpy rid in-2-y 1| -1 Ή-py razide- 3-ea rboxv lie acid (003771 Step 5. Preparation of 5-(benzo[c]fL2,5]oxadiazol-5-yl)-1-(6methylpyridin-2-yl)-l H-pyTazt)le-3-Carboxy lie acid [00378] Intermediate 5 (30 mg) was obtained through the methods of SLep 1 to Step of Preparation Example 4 using benzo[c][1.2.5]oxadiazole-5-carboxylic acid instead of quinoline-4-carboxyJic acid of Step 1.
[00379] 'HNMRspectrum (300 MHz, DMSO-d6)<i 8.14(s, I H)b 7.97-7.92( m. 2H).
7.7 l(d. lH),7.40(tL IH), 731-7.28(m, 2H), 2J0(s,3H).
[00380] <Reaction Formula 7>
[00381]
Figure AU2017289021A1_D0025
OH
- Step 4
II Ί
Step 1
Figure AU2017289021A1_D0026
Figure AU2017289021A1_D0027
Step Ξ
O OH
Figure AU2017289021A1_D0028
Step 2 q-7 -----( Step 5
Figure AU2017289021A1_D0029
Step B
Figure AU2017289021A1_D0030
Intermediate 6 [00382] [Preparation Example 6] 5-(Btnz«)i(71<jxazo]-6-yl)-l-(6-meihylpyridin2-yl)-l/f-pyrazole-3-carboxy]Ec acid
JO [00383] Step 3. Preparation of ethyl (Z)-4-(benzo[t/]oxazol-6-yl)-2-hydroxy-4oxobul-2-enoale [00384] A target compound (1.2 g] was obtained through the methods of Step 1 to
Step 3 Of Preparation Example 4 using benzo[if|oxazoie-6-carboxylic acid instead of quinoline-4-carboxylic acid of Step 1.
[00385] JH NMR spectrum (300 MHz. CDCE) δ 8.28-8.26( m, 2H), 8.06(d. 1H),
7.90(d. IH),7.27(s, IH), 7J4(s, IH). 4.42(q. 2H), 1.44(ί, 3H).
[00386] Step 4. Preparation of ethyl 5-(4-amino-3-hydroxyphenyl)-l-(6met hy lp yridin-2-yl)-1 /j-pyrazoie-3-carboxy late
Γ00387] After dissolving ethyl (Z)-4-(benzo{d]oxazoJ-fkyl)-2-hydr<}xy^koxi)but-220 enoale (1.2 g, 4.8 mmol) synthesized in Step 3 and 2-hydraziny]-6-methylpyridine hydrochloric acid (915 mg. 5.7 mmol) in ethanol (15 mL), the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and a saturated sodium bicarbonate solution was added thereto. The result was stirred for hour at room temperature, and then vacuum filtered. Obtained solids were crystallized with dichloro methane and vacuum filtered to obtain a target compound (1.5 g).
[00388] Ή NMR spectrum (300 MHz, DMSO-d6) δ 9.1 l(s, 1H), 7.84(t, 1H),
7.37(d, 1H), 7.20(d, 1H), 6.83(s, 1H), 6.49-6.41(m, 3H), 4.79(bs, 2H), 4.3l(q, 2H), 1.33(t, 3H).
[00389] Step 5. Preparation of ethyl 5-(benzor<7]oxazo 1-6-yl)-l-(6-methylpyridin2-yl)-177-p yrazole-3-carbox ylate [00390] After dissolving ethyl 5-(4-amino-3-hydroxyphenyl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxylate (1.0 g, 3.0 mmol) synthesized in Step 4 in trimethyl orthoformate (1.5 mL), the result was stirred for 2 hours at 100°C. After terminating the reaction, the reaction solution was removed under vacuum, and the result was purified using column chromatography to obtain a target compound (930 mg).
[00391] Ή NMR spectrum (300 MHz, CDC13) δ 8.12(s, 1H), 7.72-7.63(m, 2H),
7.55(d, 1H), 7.36(d, 1H), 7.25(m, 1H), 7.13(d, 1H), 7.07(s, 1H), 4.46(q, 2H), 2.33(s, 3H), 1.43(t, 3H).
[00392] Step 6. Preparation of 5-(benzor<7]oxazol-6-yl)-l-(6-methylpyridin-2-yl)177-pyrazole-3-carboxylic acid [00393] After dissolving ethyl 5-(benzo[<7]oxazol-6-yl)-l-(6-methylpyridin-2-yl)177-pyrazole-3-carboxylate (300 mg, 0.9 mmol) synthesized in Step 5 in 1,4-dioxane (3 mL), a 1 N lithium hydroxide solution (1.5 mL, 1.5 mmol) dissolved in water was introduced thereto, and the result was stirred for 2 hours at room temperature. After terminating the reaction, the reaction solution was removed under vacuum, and the result was acidified to a pH of 2 to 3 by adding 1 N hydrochloric acid thereto, and then stirred for I hour at room temperature* The result was vacuum filtered and then purified using column chromatography to obtain Intermediate 6 (10() mg)* [00394] 'H NMR spectrum (300 MHz* DMSO-dJ <5 8*75(s, 1H}, 7,85(1, 1H). 7.727.68(m. 2H), 7*45(d, 1H), 7.24-7. J 7(m, 2H), 6.84(s, IH), 2.14(s, 3H).
[00395] <Reaction Formula 8>
Figure AU2017289021A1_D0031
[Preparation Example 711-(6-MethyIpy ridin-2-y 1)-5-( 4-fluoro-3-( 1-(2|00396] [00397] hydroxy ethyl)- lH-pyrazol-4-yli-lW-pyrazoie-3-carboxylie acid [()0398] Step L Preparation of/-butyl 5-acety 1-2-Huorcpheny 1)-JH-pyr azole-i_ carboxylate [()0399] After dissolving 1 -(3-bromo-4-fluorophen yl)ethan-l -one (1 *0 g, 4.6 mmol) in 1,4-dioxane (20 mL) and water (4 mL), l-butyl 4-(4,4,5,5-tetramethyl-L3,2-dioxaboran2-yl)“lW-pyrazo!e-L-carboxylate (2*0 g, 6.9 mmol), tripotassium phosphate (2.0 g, 9.2 mmol) and XPhos (156 mg, 0.2 mmol) were added thereto under nitrogen, and the result 15 was heated under reflux for 5 hours at 1C0DC. The result was cooled to room temperature.
then extracted with ethyl acetate, dried and concentrated. The result was purified using column chromatography to obtain a target compound (960 mg)* [00400] 1H NMR (300 MHz, CDCh) 0 8.51 (s, IH), 8*21 (d, 1H), 8*14 (s, 1H), 7.23 (d, 1H), 2*64 (s, 3H), 1.70 (s, 9H).
[00401] MS (ESI+): [M+H]+ m/z 305 [00402] Step 2, Preparation of ethyl-4-(4-fluoro-3-(177-pyrazol-4-yl)phenyl)-2hydroxy-4-oxobute-2-noate [00403] After adding ethanol (15 mL) to diethyl oxalate (1.7 mL, 12.6 mmol), a 2 M ethoxysodium solution (6.3 mL, 12.6 mmol) was added thereto. ί-Butyl 4-(5-acetyl2-fluorophenyl)-l/7-pyrazole-1 -carboxylate (1.0 g, 4.6 mmol) was slowly added thereto, and the result was stirred for 3 hours at room temperature. The solvent was vacuum concentrated, and the result was acidified by adding 2 N hydrochloric acid dropwise thereto. The result was extracted with ethyl acetate, the organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated to obtain a target compound (958 mg).
[00404] Ή NMR (300 MHz, CDC13) δ 8.24 (d, 1H), 8.07 (s, 2H), 7.90-7.84 (m, 1H), 7.29-7.23 (m, 1H), 7.07 (s, 1H), 4.42 (q, 2H), 1.43 (t, 3H).
[00405] MS (ESI+): [M+H]+ m/z 305 [00406] Step 3. Preparation of ethyl 5-(4-fluoro-3-(777-pyrazol-4-yl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy late [00407] After dissolving ethyl-4-(4-fluoro-3-(177-pyrazol-4-yl)phenyl)-2-hydroxy4-oxobute-2-noate (955 mg, 3.1 mmol) and a 2-hydrazinyl-6-methylpyridine hydrochloric acid salt (751 mg, 4.7 mmol) in ethanol (15 mL), the result was stirred for 2 hours at 50°C. After terminating the reaction, the reaction solution was removed under vacuum. The result was extracted with ethyl acetate, dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (658 mg).
[00408] Ή NMR (300 MHz, CDC13) δ 7.90 (s, 2H), 7.72 (t, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.12-7.09 (m, 3H), 4.49 (q, 2H), 2.42 (s, 3H), 1.46 (t, 3H).
[00409] MS (ESI+): [M+H]+ m/z 392 [00410] Step 4, Preparation of ethyl 5-(3-(l-(2-((t-butyldimethylsilyl)oxy)ethyl)177-pyrazol-4-yl)-4-fluorophenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxylate [00411] After dissolving ethyl 5-(4-fluoro-3-(177-pyrazol-4-yl)phenyl)-l-(6methylpyridin-2-yl)-1/7- pyrazole-3-carboxylate (650 mg, 1.7 mmol), (2-bromoethoxy)(ibutyl)dimethylsilane (477 mg, 2.0 mmol) and potassium carbonate (688 mg, 5.0 mmol) in A,A-dimethylformamide (15 mL), the result was stirred for 16 hours at 80°C. The result was cooled to room temperature, then extracted with ethyl acetate, dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (740 mg).
[00412] Ή NMR (300 MHz, CDC13) δ 7.88 (s, 1H), 7.75-7.70 (m, 2H), 7.51 (d, 1H), 7.41 (d, 1H), 7.19 (d, 1H), 7.11-7.08 (m, 3H), 4.51 (q, 2H), 4.29 (t, 2H), 4.00 (t, 2H), 2.44 (s, 3H), 1.47 (t, 3H), 0.88 (s, 9H), 0.02 (s, 6H).
[00413] MS (ESI+): [M+H]+ m/z 550 [00414] Step 5. Preparation of 5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol-4vDphenyl)-1-(6- methyipyridin-2-y 1)- 177-pyrazole-3-carboxylic acid [00415] After adding an aqueous 50% ethanol solution (8 mL) to ethyl 5-(3-(1-(2((i-butyldimethylsilyl)oxy)ethyl)-177-pyrazol-4-yl)-4-fluorophenyl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxylate (700 mg, 1.3 mmol), the result was stirred for 2 hours at 50°C. The result was vacuum concentrated and acidified with 2 N hydrochloric acid, and then produced solids were filtered and dried to obtain Intermediate 7 (460 mg).
[00416] Ή NMR (300 MHz, CDC13) δ 7.84 (s, 1H), 7.74-7.69 (m, 2H), 7.50 (d, 1H), 7.40 (d, 1H), 7.18 (d, 1H), 7.08-7.05 (m, 3H), 4.32 (t, 2H), 4.06 (t, 2H), 2.40 (s, 3H). [00417] MS (ESI+): m/z 408 [M+H]+ [00418] <Reaction Formula 9>
[00419] (00420]
Figure AU2017289021A1_D0032
Figure AU2017289021A1_D0033
Figure AU2017289021A1_D0034
[Preparation Example
Figure AU2017289021A1_D0035
8] 1 -lfi-Methylpyridin-2-y l)-5-(thieno[3ac] py rid i n-2-y t)-1 //- py razole-3-car boxy lie acid [00421] Step 1. Preparation of (4-chloropvridin-3-vL methanol [00422] After dissolving 4-ch loro nicotinic acid (7*0 g, 44.4 mmol) in letrahydro furan (500 mL), lithium aluminum hydride ¢1.68 g. 44.4 mmol) was introduced thereto, and the result was stirred for 1 hour at room temperature. Aller terminating the reaction, the reaction solution was removed under vacuum, and the result was extracted by introducing ethyl acetate and water thereto* The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated* The filtrate was >1- Hpurified using Column chromatography to obtain an intermediate (2.6 g).
[00423] 'H NMR spectrum (300 MHz, CDCh) <3 8.62(s, 1H), 8.42(3, IH), 7.48(s,
1H), 7.53(s,2H)* [00424] Step 2. Preparation of 4-chloronicpt inaldehyde [00425] After dissolving (4-chloropyridin-3-yl) methanol (2*6 g, 18.0 mmol) synthesized in Step I in diehloTomethane (26 mL), manganese(IV) oxide (23.5 g, 270*5 mmol) was introduced thereto, and the result wras stirred for 12 hours al 50cC. Aller terminating the reaction, the result was extracted by introducing waler thereto* The organic layer was dried using anhydrous magnesium Sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (1.37 g).
[00426] Ή NMR spectrum (300 MHz, CDC13) δ 10.5l(s, 1H), 9.05(s, 1H), 8.67(s,
1H), 7.42(s, 1H).
[00427] Step 3. Preparation of ethylthieno[3,2,c]pyridine-2-carboxylate [00428] After dissolving 4-chloronicotinaldehyde (3.3 g, 23.3 mmol) synthesized in Step 2 in A,A-dimethylformamide (33 mL) and water (3.3 mL), potassium carbonate (3.1 g, 23.3 mmol) was introduced thereto, and the result was stirred for 5 minutes at room temperature. After adding ethyl 2-mercaptoacetate (2.8 g, 23.3 mmol) dropwise thereto, the result was stirred for 12 hours at 50°C. After the reaction was completed, water was added dropwise thereto, the result was stirred for 1 hour, and solids were filtered to obtain an intermediate (2.3 g).
[00429] Ή NMR spectrum (300 MHz, CDC13) δ 9.26(s, 1H), 8.54(s, 1H), 8.32(s, 1H), . 13(s, 1H), 4.39(q, 2H), 1.33(t, 3H).
[00430] Step 4, Preparation of thieno[3,2-c]pyridine-2-carboxylic acid [00431] After dissolving ethylthieno[3,2,c]pyridine-2-carboxylate (2.3 g, 11.0 mmol) synthesized in Step 3 in methanol (25 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70°C. After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid thereto, and then extracted by introducing chloroform/isopropanol (3:1) thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain an intermediate (1.89 g).
[00432] Ή NMR spectrum (300 MHz, CDC13) δ 9.24(s, 1H), 8.52(s, 1H), 8.23(s,
1H), 8.10(s, 1H).
[00433]
Step 5. Preparation of A-methoxy-A-methylthienor3,2-c]pyridine-2carboxyamide [00434] After adding thieno[3,2-c]pyridine-2-carboxylic acid (1.9 g, 10.5 mmol), HATU (6.0 g, 15.8 mmol) and TEA (3.2 g, 31.6 mmol) to dichloromethane (38 mL) and MAM i methyl for mam ide (7.5 mL), the result was stirred for 30 minutes. To the reaction solution, an N, O-dimethylhydroxylamine salt (1.1 g, 11.6 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, the reaction solution was removed, and ethyl acetate was added thereto. The result was washed with water and saline, then dried using anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (1.4 g).
[00435] Ή NMR spectrum (300 MHz, CDC13) δ 9.19(s, 1H), 8.50(s, 1H), 8.27(s,
1H), 7.80(s, 1H), 3.83(s, 3H), 3.42(s, 3H).
[00436] Step 6. Preparation of l-(thieno[3,2-c]pyridin-2-yl)ethan-l-one [00437] After dissolving A-methoxy-A-methylthieno[3,2-c]pyridine-2carboxyamide (0.4 g, 1.7 mmol) synthesized in Step 5 in anhydrous tetrahydrofuran (5.1 mL) under argon, 3 M methyl magnesium bromide (2.8 mL, 2.5 mmol) dissolved in diethyl ether was added drop wise thereto at 0°C. After terminating the reaction by introducing a saturated ammonium chloride solution thereto, ethyl acetate was introduced thereto, and the result was extracted. The organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and then purified using column chromatography to obtain a target compound (250 mg).
[00438] Ή NMR spectrum (300 MHz, CDC13) δ 9.19(s, 1H), 8.54(s, 1H), 7.80(s,
1H), 7.78(s, 1H), 2.68(s, 3H).
[00439]
Step 7. Preparation of (Z)-ethyl 2-hydroxy-4-oxo-4-(thieno[3,2-c]pyridin2-yl)2-butenoate [00440] After dissolving l-(thieno[3,2-c]pyridin-2-yl)ethan-1-one (0.3 g, 1.4 mmol) synthesized in Step 6 and diethyl oxalate (0.8 g, 5.6 mmol) in ethanol (2.5 mL), ethoxysodium (0.4 g, 5.6 mmol) was slowly added dropwise thereto at 50°C, and the result was refluxed for 2 hours. After cooling the result to room temperature, the solvent was vacuum concentrated, and the result was acidified by adding 2 M hydrochloric acid dropwise thereto. Dichloro methane was introduced thereto for extraction, and the organic layer was dried using anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (0.2 g).
[00441] Ή NMR spectrum (300 MHz, CDC13) δ 9.5l(s, 1H), 8.43(s, 1H), 8.16(s,
1H), 7.38(s, 1H), 7.38 (s, 1H), 4.23(q, 2H), 1.21(t, 3H).
[00442] Step 8. Preparation of ethyl l-(6-methylpyridin-2-yl)-5(thieno[3,2,c]pyridin-2-yl)-177-pyrazole-3-carboxylate [00443] After dissolving (Z)-ethyl 2-hydroxy-4-oxo-4-(thieno[3,2-c]pyridin-2yl)2-butenoate (0.2 g, 0.6 mmol) synthesized in Step 7 and 2-hydrazinyl-6-methylpyridine hydrochloric acid (0.1 g, 0.6 mmol) in ethanol (1.5 mL), the result was refluxed for 2 hours. After terminating the reaction, the reaction solution was removed under vacuum, and ethyl acetate was added thereto. The organic layer was washed with saline and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (98 mg).
[00444] Ή NMR spectrum (300 MHz, CDC13) δ 9.02(s, 1H), 8.45(s, 1H), 7.847.70(m, 2H), 7.61(t, 1H), 7.52(s, 1H), 7.39-7.20(m, 2H), 4.50(q, 2H), 2.32(s, 3H), 1.43(t, 3H).
[00445]
Step 9. Preparation of l-(6-mcthylpyridin-2-yl)-5-(thicno|3.2-c|pyridin-2yl)-177-pyrazolc-3-carboxyl ic acid [00446] After dissolving ethyl l-(6-methylpyridin-2-yl)-5-(thieno[3,2,c]pyridin-2yl)-177-pyrazole-3-carboxylate (98 mg, 0.3 mmol) synthesized in Step 8 in 1,4-dioxane (1 mL), a 2 N lithium hydroxide solution dissolved in water was introduced thereto, and the result was stirred for 2 hours at 70°C. After terminating the reaction, the reaction solution was removed under vacuum. The result was acidified by adding 12 N hydrochloric acid thereto, and then extracted by introducing chloroform/isopropanol (3:1) thereto. The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain Intermediate 8 (82 mg).
[00447] Ή NMR spectrum (300 MHz, CDC13) δ 9.50(s, 1H), 8.69(d, 2H), 8.06(s, 1H), 7.99(t, 1H), 7.64-7.61(m, 2H), 7.43 (d, 1H), 2.37(s, 3H).
[00448] [Example 1] 5 - (Benzo [ d\ thiazo 1- 6- yl) -N- (4- methoxyphenyl) -1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide [00449]
Figure AU2017289021A1_D0036
Figure AU2017289021A1_D0037
[00450]
After dissolving l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177 pyrazole-3-carboxylic acid (40 mg, 0.1 mmol) synthesized in Step 5 of Preparation
Example 1 in dichloromethane, HATU (54 mg, 0.1 mmol) and DIPEA (60 pL, 0.4 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature. To the reaction solution, p-anisidine (16 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (22 mg).
[00451] Ή NMR spectrum (300 MHz, CDC13) δ 9.05(s, 1H), 8.76(s, 1H), 8.05(d,
1H), 7.98(d, 1H), 7.66-7.63(m, 3H), 7.35(dd, 1H), 7.20(t, 3H), 7.20(dd, 2H), 3.82(s, 3H), 2.43(s, 3H).
[00452] MS (ESI+): [M+H]+ m/z 442.1 [00453] [Examples 2 to 81] [00454] Compounds of Examples 2 to 79 listed in the following [Table 1] were obtained in the same manner as in Step 1) of Example 1 using various amine derivatives instead of p-anisidine.
[00455] [Table 1]
Example Number Structure Compound Name ’H NMR Spectrum (300 MHz, CDChk) MS (ES) Actual Measurement Value[M+H]+/ Required Value
2 A 'A ° 5-(benzo[d]thiazol-6-yl)- N-(4-ethoxyphenyl)-l(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.04(s, 1H), 8.73(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.69-7.60(m, 3H), 7.36(dd, 1H), 7.19(t, 3H), 6.90 (d, 2H), 4.04(q, 2H), 2.42(s, 3H), 1.41(t, 3H) 456.1/455.1
3 A ΗΝ-Ζ=\-0 5-(benzo[i/]thiazol-6-yl)- Ν-(4(cyclopropylmethoxy)ph enyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.74(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.69-7.61(m, 3H), 7.36(dd, 1H), 7.22(1, 3H), 6.92(d, 2H), 3.80(d, 2H), 2.44(s, 3H), 1.28-1.21(m, 1H), 0.66(q, 2H), 0.36(q, 2H) 482.2/481.2
4 5-(benzo[i/]thiazol-6-yl)- N-(4-(2methoxyethoxy)phenyl) - 1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide 9.04(s, 1H), 8.77(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.68-7.61(m, 3H), 7.36(dd, 1H), 7.20(1, 3H), 6.95(d, 2H), 4.14-4.11(m, 2H), 3.77- 3.73(m, 2H), 3.46(s, 3H), 2.42(s, 3H) 486.2/485.2
5 A χ ^ajA ) °cF3 νΆ^ 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4(trifluoromethoxy)pheny l)-lH-pyrazole-3carboxyamide 9.05(s, 1H), 8.88(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.76(d, 2H), 7.67(t, 1H), 7.36(dd, 1H), 7.25-7.19(m, 5H), 2.45(s, 3H) 496.1/495.1
6 A \|Α^ 5-(benzo[i/]thiazol-6-yl)- N-(4- (benzyloxy)phenyl) -1 - (300 MHz, DMSO-d6)<5 10.15(s, 1H), 9.44(s, 1H), 8.26(d, 1H), 8.03(d, 1H), 518.2/517.2
(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 7.92(t, 1H), 7.73(d, 2H), 7.61(d, 1H), 7.47-7.32(m, 6H), 7.20(s, 1H), 7.00(d, 2H), 5.10(s, 2H), 2.22(s, 3H)
7 N -(benzo[i/][l,3]dioxol- 5-yl)-5-(benzo[i/]thiazol- 6-yl)-1-(6methylpyridin-2-yl)-1 H-pyrazole-3carboxyamide 9.05(s, 1H), 8.75(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.66(1, 1H), 7.45(d, 1H), 7.34(dd, 1H), 7.18(1, 3H), 7.00(d, 1H), 6.70(d, 1H), 5.97(s, 2H), 2.44(s, 3H) 456.1/455.1
8 0 » V-V n-njhn-4 \ f p 5-(benzo[i/]thiazol-6-yl)- N-(4-fluoro-3methoxyphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.81(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.74-7.64(m, 2H), 7.35(dd, 1H), 7.22(t, 3H), 7.02(d, 2H), 3.94(s, 3H), 2.44(s, 3H). 460.1/459.1
9 d „ >. γγίλ 5-(benzo[i/]thiazol-6-yl)- N-(2-fluoro-4methoxyphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.04(s, 1H), 8.88(s, 1H), 8.30(1, 1H), 8.05(d, 1H), 7.99(d, 1H), 7.69(1, 1H), 7.35(t, 2H), 7.18-7.15(m, 2H), 6.70(d, 2H), 3.80(s, 3H), 2.36(s, 3H) 460.1/459.1
10 d „ <syYK^' 5-(benzo[i/]thiazol-6-yl)- N-(3-fluoro-4- 9.04(s, 1H), 8.77(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 460.1/459.1
methoxyphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 7.69-7.63(m, 2H), 7.35(d, 2H), 7.19(t, 3H), 6.95(t, 1H), 3.89(s, 3H), 2.43(s, 3H)
11 ^N-NHNSn 5-(benzo[i/]thiazol-6-yl)- N-(3-aminophenyl)-l(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide (300 MHz, DMSO-d6) δ 10.50(s, 1H), 9.41(s, 1H), 8.25(s, 1H), 8.02(m, 1H), 7.91(t, 1H), 7.68(d, 1H), 7.59(d, 1H), 7.43-7.32(m, 4H), 7.03(d, 1H), 2.22(s, 3H) 427.1/426.1
12 A 5-(benzo[i/]thiazol-6-yl)- N-(3(methylamino)phenyl) - 1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide (300 MHz, MeOD) δ 9.30(s, 1H), 8.11(s, 1H), 8.02(d, 1H), 7.80(t, 1H), 7.42-7.37(m, 2H), 7.31(d, 1H), 7.17(s, 1H), 7.14-7.09(m, 2H), 7.00(d, 1H), 6.45(d, 1H), 2.80(d, 3H), 2.36(s, 3H) 441.1/440.1
13 A< ^V>4N-O\ 0 5-(benzo[i/]thiazol-6-yl)- N-(4(dimethylamino)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.04(s, 1H), 8.71(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.66(t, 1H), 7.59(d, 2H), 7.36(dd, 1H), 7.23-7.16(m, 3H), 6.76(d, 2H), 2.95(s, 6H), 2.05(s, 3H) 455.2/454.2
14 ό. ^Ν-ΝηΝ-Ζ^-ΝΟζ 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4-nitrophenyl)lH-pyrazole-3carboxyamide (300 MHz, DMSO-d6)<5 10.90(s, 1H), 9.45(s, 1H), 8.29-8.26(m, 3H), 8.15(d, 2H), 8.05(d, 1H), 7.93(t, 1H), 7.61(d, 1H), 7.38-7.34(m, 2H), 7.31(s, 1H), 2.27(s, 3H) 457.1/456.1
15 <ίΝ 'Ν /) Ν\ 7 5-(benzo[i/]thiazol-6-yl)- N-(4-((2- (dimethylamino)ethyl)( methyl)amino)phenyl)- 1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide 9.04(s, 1H), 8.68(s, 1H), 8.04(d, 1H), 7.98(d, 1H), 7.66(t, 1H), 7.56(d, 2H), 7.35(d, 1H), 7.20(t, 3H), 6.74(d, 2H), 3.48(t, 2H), 2.96(s, 3H), 2.55(1, 2H), 2.43(s, 3H), 2.35(s, 6H) 490.1/489.1
16 5-(benzo[i/]thiazol-6-yl)- N-(4-(3(dimethylamino)pyrrolid in-1 -yl)phenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.67(s, 1H), 8.07(d, 1H), 7.99(s, 1H), 7.67(t, 1H), 7.59(d, 2H), 7.38(d, 1H), 7.35-7.17(m, 3H), 6.58(d, 2H), 3.55- 3.41(m,2H), 3.37-3.34(m, 1H), 3.20(1, 1H), 2.93- 2.91(m, 1H), 2.43(s, 3H), 2.36(s, 6H), 2.24-2.22(m,lH) 524.2/523.2
17 0 Γ <CI 5-(benzo[i/]thiazol-6-yl)- N-(3-chloro-4- 9.04(s, 1H), 8.70(s, 1H), 8.04(d, 1H), 7.97(s, 1H), 570.1/569.1
(octahydro-6Hpyrrolo[3,4-b]pyridin-6yl)phenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 7.74(s, 1H), 7.60(t, 1H), 7.44(d, 1H), 7.34(d, 1H), 7.24-7.15(m, 3H), 6.86(d, 1H), 3.80-3.70(m,2H), 3.47- 3.45(m,3 H), 3.30-3.06(m, 2H), 2.70(t, 1H), 2.41(s, 3H), 2.392.36(m, 1 H), 1.77-1.73(m,3H)
18 €0^· 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-phenyl-1Hpyrazole-3carboxyamide 9.08(s, 1H), 8.89(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.74(d, 2H), 7.66(t, 1H), 7.38-7.35(m, 3H), 7.22- 7.17(m, 4H), 2.43(s, 3H) 412.1/411.1
19 d N « <SXT^ H 5-(benzo[i/]thiazol-6-yl)- N-(3-tolyl)-1-(6- methylpyridin-2-yl)-lHpyrazole-3carboxyamide (300 MHz, MeOD) δ 9.28(s, 1H), 8.06(s, 1H), 7.98(d, 1H), 7.76(t, 1H), 7.56-7.53(m, 2H), 7.36(d, 2H), 7.30- 7.20(m, 2H), 7.13(s, 1H), 6.96(d, 1H), 2.34(s, 3H), 2.33(s, 3H) 426.1/425.1
20 Γ'Ν /= 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(3-vinylphenyl)- 9.05(s, 1H), 8.85(s, 1H), 8.05(d, 1H), 7.99(d, 1H), 7.90(s, 1H), 7.70-7.62(m, 438.1/437.1
1 //-pyrazolc-3- carboxyamide 2H), 7.34(d, 2H), 7.21(t, 3H), 6.73(dd, 1H), 5.80(d, 1H), 5.28(d, 1H), 2.43(s, 3H)
21 A 5-(benzo[i/]thiazol-6-yl)- N-(3(trifluoromethyl)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.06(s, 1H), 9.01(s, 1H), 8.08-8.05(m, 2H), 8.00- 7.94(m, 2H), 7.68(t, 1H), 7.50(t, 1H), 7.41-7.34(m, 2H), 7.28-7.19(m, 3H), 2.45(s, 3H) 480.1/479.1
22 /^N CN A<-nhn--Q 5-(benzo[i/]thiazol-6-yl)- N-(3-(cyanophenyl)-l(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.06(s, 1H), 8.95(s, 1H), 8.15(d, 1H), 8.06(d, 1H), 7.99(d, 1H), 7.80(dd, 1H), 7.68(t, 1H), 7.47-7.43(m, 2H), 7.37(dd, 1H), 7.21- 7.18(m, 3H), 2.45(s, 3H) 437.1/436.1
23 A FViN-O x < a 5-(benzo[i/]thiazol-6-yl)- N-(3-acetylphenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.07(s, 1H), 9.01(s, 1H), 8.27(s, 1H), 8.26-8.06(m, 2H), 8.00(s, 1H), 7.74- 7.67(m, 2H), 7.50(t, 1H), 7.38(d, 1H), 7.25-7.20(m, 2H), 2.66(s, 3H), 2.45(s, 3H) 454.1/453.1
24 ^N VoEt δο^Ν~θ ethyl 3-(5- (benzo[i/]thiazol-6-yl)-l- (6-methylpyridin-2-yl)- 9.05(s, 1H), 8.95(s, 1H), 8.21(s, 1H), 8.16(d, 1H), 8.06(d, 1H), 7.99(d, 1H), 484.1/483.1
lH-pyrazole-3- carboxyamido)benzoate 7.83(d, 1H), 7.66(t, 1H), 7.46(t, 1H), 7.37(dd, 1H), 7.21 (t, 3H), 4.40(q, 2H), 2.43(s, 3H), 4.41(t, 3H)
5-(benzo[i/]thiazol-6-yl)- 9.05(s, 1H), 8.98(s, 1H),
N-(4- 8.07(d, 1H), 7.99(d, 1H),
(methylcarbamoyl)phen 7.80(s, 4H), 7.68(t, 1H),
25 ^n-n hn-Z \ HN yl)-1 -(6-methylpyridin- 7.35(dd, 1H), 7.21 (t, 3H), 469.1/468.1
2-yl)-1 H-pyrazole-3- 6.10(s, 1H), 3.03(d, 3H),
carboxyamide 2.44(s, 3H)
(300 MHz, DMSO-d6) δ
10.16(s, 1H), 9.90(s, 1H),
5-(benzo[i/]thiazol-6-yl)- 9.42(s, 1H), 8.85(d, 1H),
/ N-(4- 8.39(d, 1H), 8.25(s, 1H),
ό V acetoamidophenyl)-1 -(6-
26 ''Αί-Ν^ΗΝ-^ Jhi/h 8.25-8.00(m, 2H), 7.90(t, 469.1/468.1
methylpyridin-2-yl)-lH- 1H), 7.73(d, 2H), 7.60(d,
pyrazole-3- 1H), 7.53(d, 2H), 7.34(t, 2H),
carboxyamide 7.19(s, 1H), 2.21(s, 3H),
2.01(s, 3H)
5-(benzo[i/]thiazol-6-yl)- 9.10(br, 1H), 9.05(s, 1H),
27 / N F\ ^N-VjN-b N-(2-fluorophenyl)-1-(6- methylpyridin-2-yl)-lH- 8.52(t, 1H), 8.06(d, 1H), 8.00(d, 1H), 7.70(t, 1H), 430.1/429.1
pyrazole-3- 7.39-7.35(m, 2H), 7.20-
carboxyamide 7.09(m, 5H), 2.35(s, 3H)
28 / N F 5-(benzo[i/]thiazol-6-yl)- N-(3-fluorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.91(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.79-7.65(m, 2H), 7.37- 7.30(m, 3H), 7.23-7.18(m, 3H), 6.84(1, 1H), 2.44(s, 3H) 430.1/429.1
29 A 5-(benzo[i/]thiazol-6-yl)- N-(4-fluorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.84(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.72-7.67(m, 3H), 7.36(d, 1H), 7.22-7.18(m, 3H), 7.07(t, 2H), 2.44(s, 3H) 430.1 /429.1
30 ζ ,N F x fv?O-' 5-(benzo[i/]thiazol-6-yl)- N-(3,4-difluorophenyl)- 1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide 9.06(s, 1H), 8.86(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.82-7.78(m, 1H), 7.67(t, 1H), 7.35(d, 1H), 7.30- 7.28(m, 1H), 7.21-7.13(m, 4H), 2.45(s, 3H) 448.1/447.1
31 d N „ N'VJzN~y ) 5-(benzo[i/]thiazol-6-yl)- N-(2-chlorophenyl)-1 (6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.49(s, 1H), 9.05(s, 1H), 8.60(d, 1H), 8.05(d, 1H), 8.01(d, 1H), 7.73(1, 1H), 7.46-7.34(m, 4H), 7.19(s, 1H), 7.15 (d, 1H), 7.07(t, 1H), 2.30(s, 3H) 446.1/445.1
32 A ^Ν-ΝΗΝ-θ ci 5-(benzo[i/]thiazol-6-yl)- N-(3-chlorophenyl)-l(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.05(s, 1H), 8.85(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.86(s, 1H), 7.67(t, 1H), 7.57(d, 1H), 7.36-7.30(m, 2H), 7.21-7.10(m, 4H), 2.44(s, 3H) 446.1/445.1
33 Αν ^^NOCI 5-(benzo[i/]thiazol-6-yl)- N-(4-chlorophenyl)-1 (6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.05(s, 1H), 8.84(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.70-7.64(m, 3H), 7.367.30(m, 3H), 7.21-7.18(m, 3H), 2.44(s, 3H) 446.1/445.1
34 A χ ν-^νΟβγ Ν^4 5-(benzo[i/]thiazol-6-yl)- N-(4-bromophenyl) -1 (6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.05(s, 1H), 8.83(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.69-7.62(m, 3H), 7.48(d, 2H), 7.34(d, 1H), 7.21- 7.18(m, 3H), 2.44(s, 3H) 490.0/489.0
35 A 's χ JA4n~A 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(3- (methylthio)phenyl)- 1H- pyrazole-3- carboxyamide 9.04(s, 1H), 8.84(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.74(m, 1H), 7.67(t, 1H), 7.40(dd, 1H), 7.35(d, 1H), 7.27-7.17(m, 4H), 7.01(d, 1H), 2.52(s, 3H), 2.43(s, 3H) 458.1/457.1
36 A <®γγΆ> 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- 9.05(s, 1H), 8.84(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 458.1/457.1
yl)-N-(4- (methylthio)phenyl)-1Hpyrazole-3carboxyamide 7.69-7.64(m, 3H), 7.36- 7.27(m, 4H), 7.21-7.18(m, 2H), 2.49(s, 3H), 2.44(s, 3H)
37 A 5-(benzo[i/]thiazol-6-yl)- N-(4(cyclopropylthio)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.04(s, 1H), 8.8O(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.69-7.64(m, 3H), 7.40- 7.34(m, 4H), 7.26-7.17(m, 2H), 2.43(s, 3H), 2.23- 2.19(m, 1H), 1.08-1.03(m, 2H), 0.73-0.69(m, 2H)
38 ° 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(3(methylsulfinyl)phenyl)lH-pyrazole-3carboxyamide 9.09(s, 1H), 9.05(s, 1H), 8.07-7.98(m, 4H), 7.69(t, 1H), 7.54(1, 1H), 7.43- 7.34(m, 2H), 7.20-7.18(m, 3H), 2.77(s, 3H), 2.42(s, 3H) 474.1/473.1
39 A ςΥΑ^ο δ 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4(methylsulfinyl)phenyl)lH-pyrazole-3carboxyamide 9.08(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.93(d, 2H), 7.69-7.64(m, 3H), 7.36(d, 1H), 7.22- 7.17(m, 3H), 2.74(s, 3H), 2.46(s, 3H) 474.1/473.1
40 A \-V f ό 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(3(methylsulfonyl)phenyl) -1 //-pyrazolc-3carboxyamide 9.07(m, 2H), 8.24(s, 1H), 8.15(d, 1H), 8.06(d, 1H), 7.99(d, 1H), 7.69(1, 2H), 7.59(1, 1H), 7.36(d, 1H), 7.22-7.19(m, 3H), 3.10(s, 3H), 2.44(s, 3H) 490.1/489.1
41 A ?Τί^ 0 ό 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4(methylsulfonyl)phenyl) -lH-pyrazole-3carboxyamide 9.12(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 7.98-7.95(m, 5H), 7.67(t, 1H), 7.35(d, 1H), 7.22-7.18(m, 3H), 3.07(s, 3H), 2.46(s, 3H) 490.1/489.1
42 A x N-N HN-/ \ S=° to^ 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(4(propylsulfonyl)phenyl) lH-pyrazole-3carboxyamide 9.10(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 7.99-7.89(m, 5H), 7.68(t, 1H), 7.35(d, 1H), 7.23-7.17(m, 3H), 3.10- 3.05(m, 2H), 2.46(s, 3H), 1.80-1.72(m, 2H), 1.01(t, 3H) 518.1/517.1
43 A 354N^<° 5-(benzo[i/]thiazol-6-yl)- N-(4(cyclopropylsulfonyl)ph enyl)-1-(6methylpyridin-2-yl)-lH- 9.08(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.95-7.91(m, 4H), 7.68(t, 1H), 7.35(d, 1H), 7.22- 7.18(m, 3H), 2.49-2.46(m, 516.1/515.1
pyrazole-3carboxyamide 4H), 1.37-1.35(m, 2H), 1.06- 1.02(m, 2H)
44 / N F\ 5-(benzo[i/]thiazol-6-yl)- N-(2-fluoro-4(methylsulfonyl)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.36(s, 1H), 9.07(s, 1H), 8.86(t, 1H), 8.07(d, 1H), 8.01(s, 1H), 7.82-7.70(m, 3H), 7.39-7.32(m, 3H), 7.22- 7.20(m, 2H), 3.09(s, 3H), 2.39(s, 3H) 508.0/507.0
45 A s^o N^ H2tf 0 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(3sulfamoylphenyl) -1Hpyrazole-3carboxyamide 9.12(s, 1H), 8.34(m, 1H), 8.08(d, 1H), 8.02(d, 1H), 7.98(d, 1H), 7.70-7.60(m, 2H), 7.52(t, 1H), 7.37(d, 1H), 7.24(d, 1H), 7.20(s, 2H), 6.98(d, 1H), 2.56(s, 3H) 491.1/490.1
46 f N VA /=\ 9 N'N hn-< /)-s--o S NH2 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4sulfamoylphenyl) -1Hpyrazole-3carboxyamide 9.12(s, 1H), 8.07(d, 1H), 8.01(d, 1H), 7.93(s, 4H), 7.64(t, 1H), 7.39-7.26(m, 2H), 7.24(d, 1H), 7.21(s, 1H), 7.00(d, 1H), 2.56(s, 3H) 491.1/490.1
47 A ,S NH 4i-V °δ ' 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(3-(N - methylsulfamoyl)phenyl 9.06-7.05(m, 2H), 8.18(d, 1H), 8.05(d, 2H), 7.99(d, 1H), 7.71-7.54(m, 3H), 7.35(d, 1H), 7.24-7.20(m, 505.1/504.1
)-l/7-pyrazole-3- carboxyamide 3H), 4.41-4.39(bs, 1H), 2.73(s, 3H), 2.44(s, 3H)
48 Q /=\ 0 N-N HN-O-S'-O ATM. X / HN- 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(4-(7Vmethylsulfamoyl)phenyl )-l/7-pyrazole-3carboxyamide 9.06 (m, 2H), 8.06(d, 1H), 7.99(d, 1H), 7.93-7.85(m, 3H), 7.68(t, 1H), 7.35(d, 1H), 7.22-7.18(m, 3H), 4.21- 4.19(bs, 1H), 2.69(s, 3H), 2.46(s, 3H) 505.1/504.1
49 Aj ^n-v^-O 0 o-r^ 5-(benzo[i/]thiazol-6-yl)- N-(3-(Ncyclopropylsulfamoyl)p henyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.06(s, 1H), 9.05(s, 1H), 8.19(d, 1H), 8.08(t, 2H), 7.99(d, 1H), 7.70-7.66(m, 2H), 7.55(t, 1H), 7.35(d, 1H), 7.22-7.19(m, 3H), 4.91(s, 1H), 2.44(s, 3H), 2.35- 2.28(m, 1H), 0.68-0.64(m, 4H) 531.1/530.1
50 A ^^N-N hnA \ s»O 5-(benzo[i/]thiazol-6-yl)- N-(4-(Ncyclopropylsulfamoyl)p henyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.13(s, 1H), 9.06(s, 1H), 8.07(d, 1H), 8.00(d, 1H), 7.85(d, 2H), 7.71(t, 1H), 7.42-7.34(m, 2H), 7.21- 7.17(m, 4H), 4.90(s, 1H), 2.34(s, 3H), 2.25-2.22(m, 1H), 0.60-0.57(m, 4H) 531.1/530.1
51 A 5-(benzo[i/]thiazol-6-yl)- N-(3-(N,N dimethylsulfamoyl)phen yl)-1 -(6-methylpyridin2-yl)-1 H-pyrazole-3carboxyamide 9.08(s, 1H), 9.06(s, 1H), 8.10-8.05(m, 3H), 7.98(d, 1H), 7.68(t, 1H), 7.56- 7.54(m, 2H), 7.35(d, 1H), 7.25-7.19(m, 3H), 2.76(s, 6H), 2.44(s, 3H) 519.1/518.1
52 4» 5-(benzo[i/]thiazol-6-yl)- N-(4-(N, Ndimethylsulfamoyl)phen yl)-1 -(6-methylpyridin2-yl)-1 H-pyrazole-3carboxyamide (300 MHz, DMSO-d6) δ 10.50(s, 1H), 9.23(s, 1H), 8.46(s, 1H), 8.02(m, 1H), 7.96(d, 2H), 7.89-7.85(m, 3H), 7.60(d, 2H), 7.34-7.29 (m, 1H), 7.25-7.22(m, 1H), 2.66(s, 6H), 2.51(s, 3H) 519.1/518.1
53 0 /=, n-nhn-Z \ 5 n-O 50 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(3(methylsulfonamide)phe nyl)-1 H-pyrazole-3 carboxyamide 9.05(s, 1H), 8.90(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.77(d, 1H), 7.68(t, 1H), 7.48(d, 1H), 7.38-7.34(m, 2H), 7.23-7.18(m, 3H), 7.00(d, 1H), 6.40(s, 1H), 3.06(s, 3H), 2.43(s, 3H) 505.1/504.1
54 A OCr^ Λ4 5-(benzo[i/]thiazol-6-yl)- N-(3- (cyclopropanesulfonami do)phenyl)-1-(6- 9.05(s, 1H), 8.89(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.80(d, 1H), 7.67(t, 1H), 7.48(d, 1H), 7.35(d, 2H), 531.1/530.1
methylpyridin-2-yl)-lH- pyrazole-3carboxyamide 7.23-7.18(m, 3H), 7.06(d, 1H), 6.32(s, 1H), 2.56- 2.54(m, 1H), 2.43(s, 3H), 1.28-1.21(m, 2H), 1.04- 0.99(m, 2H)
55 A A< ° 5-(benzo[i/]thiazol-6-yl)- N-(4(cyclopropanesulfonami do)phenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.06(s, 1H), 8.87(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.72(d, 2H), 7.67(t, 1H), 7.35(d, 1H), 7.30(d, 2H), 7.23-7.18(m, 3H), 6.32(s, 1H), 2.49-2.44(s, 4H), 1.18- 1.15(m, 2H), 1.00-0.95(m, 2H) 531.1/530.1
56 Ca /=\ 9 4-(5-(benzo[i/]thiazol-6- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamido)benzenes ulfonic acid (300 MHz, DMSO-d6)<5 10.30(s, 1H), 9.44(s, 1H), 8.27(d, 1H), 8.03(d, 1H), 7.93(t, 1H), 7.77(d, 2H), 7.65(d, 1H), 7.56(d, 2H), 7.34(t, 2H), 7.23(s, 1H), 2.08(s, 3H) 492.1/491.1
57 A A-NΗΝ-ΓΎ-έ-0 s 'cf3 <Ύί 0 n-O 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(4- ((trifluoromethyl)sulfon 9.23(s, 1H), 9.06(s, 1H), 8.08-8.04(m, 5H), 7.99(d, 1H), 7.68(1, 1H), 7.35(d, 1H), 544.1/543.1
yl)phenyl)-1 H-pyrazole- 3-carboxyamide 7.24-7.17(m, 3H), 2.47(s, 3H)
58 Ca /=\ 9 N-K hnA ksfO «Xj ° cp3 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4-(2V- (2,2,2trifluoroethyl)sulfamoyl) phenyl)-1 //-pyrazolc-3carboxyamide 9.09(s, 1H), 9.06(s, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.89(dd, 4H), 7.68(1, 1H), 7.36(d, 1H), 7.22-7.19(m, 3H), 4.97(1, 1H), 3.73- 3.65(m, 2H), 2.45(s, 3H)
59 a A/A -s °'o 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4((methylsulfonyl)methyl )phenyl) -1 H-pyr azole-3 carboxyamide 9.05(s, 1H), 8.93(s, 1H), 8.06(d, 1H), 7.99(d, 1H), 7.85(d, 1H), 7.75(d, 1H), 7.68(t, 1H), 7.43(t, 2H), 7.37(d, 1H), 7.23-7.18(m, 3H), 4.27(s, 2H), 2.81(s, 3H), 2.43(s, 3H) 504.1/503.1
60 A A° x λ>4νΑΓ NH2 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(3(sulfamoylmethyl)pheny l)-lH-pyrazole-3carboxyamide (300 MHz, DMSO-d6)<5 10.31(s, 1H), 9.45(s, 1H), 8.27(d, 1H), 8.03(d, 1H), 7.95-7.84(m, 3H), 7.64(d, 1H), 7.39-7.33(m, 3H), 7.24(s, 1H), 7.12(d, 1H), 6.88(s, 2H), 4.25(s, 2H), 2.22(s, 3H) 505.1/504.1
61 A A A οΤνη’ 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(4(sulfamoylmethyl)pheny 1)-1 //-pyrazolc-3carboxyamide (300 MHz, DMSO-d6)<5 10.32(s, 1H), 9.45(s, 1H), 8.27(d, 1H), 8.03(d, 1H), 7.92(t, 1H), 7.84(d, 2H), 7.61(d, 1H), 7.35-7.33(m, 4H), 7.24(s, 1H), 6.83(s, 2H), 4.23(s, 2H), 2.23(s, 3H) 505.1/504.1
62 A A0 x ΓMA pNH2 /χΑ-η ν-Ά^ 5-(benzo[i/]thiazol-6-yl)- N-(4-fluoro-3(sulfamoylmethyl)pheny 1)-1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide (300 MHz, DMSO-d6)<5 10.40(s, 1H), 9.45(s, 1H), 8.27(d, 1H), 8.03(d, 1H), 7.97-7.90(m, 3H), 7.62(d, 1H), 7.35(dd, 2H), 7.23(dd, 2H), 7.06(s, 2H), 4.30(s, 2H), 2.23(s, 3H) 523.1/522.1
63 A 'ivjin~CYn h ν-^ύ o 5-(benzo[i/]thiazol-6-yl)- N-(4-((l,l- dioxidotetrahydrothioph en-3-yl)amino)phenyl)- 1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide 9.05(s, 1H), 8.85(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.68(t, 1H), 7.62(d, 2H), 7.37(d, 1H), 7.23-7.18(m, 3H), 6.70(d, 2H), 4.25(s, 1H), 3.45-2.98(m, 5H), 2.55- 2.50(m, 1H), 2.43(s, 3H), 2.33-2.30(m, 1H) 545.1/544.1
64 A 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(pyridin-4-yl)-lH- pyrazole-3- carboxyamide 9.05(s, 1H), 8.96(s, 1H), 8.55(d, 2H), 8.05(d, 1H), 7.98(d, 1H), 7.70-7.65(m, 3H), 7.35(d, 1H), 7.22- 7.19(m, 3H), 2.44(s, 3H) 413.1/412.1
65 A 5-(benzo[i/]thiazol-6-yl)- N-(6-methoxypyridin-3- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide 9.05(s, 1H), 8.74(s, 1H), 8.38(d, 1H), 8.13(dd, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.66(1, 1H), 7.35(d, 1H), 7.21(s, 2H), 7.18(dd, 1H), 6.79(d, 1H), 3.94(s, 3H), 2.45(s, 3H) 443.1/442.1
66 A y-v^O A 5-(benzo[i/]thiazol-6-yl)- N-(2-methoxypyridin-4- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide 9.06(s, 1H), 8.95(s, 1H), 8.11-8.04(m, 2H), 7.97(d, 1H), 7.67(t, 1H), 7.34(d, 1H), 7.22-7.17(m, 5H), 3.95(s, 3H), 2.45(s, 3H) 443.1/442.1
67 A A-n <-μ n-^A^ 5-(benzo[i/]thiazol-6-yl)- N-(6- (methylthio)pyridin-3- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide 9.07(s, 1H), 8.83(s, 1H), 8.67(s, 1H), 8.18(d, 1H), 8.07(d, 1H), 7.99(s, 1H), 7.68(1, 1H), 7.36(d, 1H), 7.24-7.20(m,4H), 2.59(s, 3H), 2.46(s, 3H) 459.1/458.1
68 Ca Ν /=\ ' '0 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(6- (methylsulfonyl)pyridin- 2-yl)-1 H-pyrazole-3- carboxyamide 9.64(s, 1H), 9.06(s, 1H), 8.68(d, 1H), 8.08-7.99(m, 3H), 7.84(d, 1H), 7.73(t, 1H), 7.35(d, 2H), 7.22-7.13(m, 2H), 3.22(s, 3H), 2.32(s, 3H) 491.1/490.1
69 ό 5-(benzo[i/]thiazol-6-yl)- N-(6(methylsulfonyl)pyridin3-yl)-l-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.16(s, 1H), 9.06(s, 1H), 8.92(s, 1H), 8.60(d, 1H), 8.12-8.05(m, 2H), 7.98(s, 1H), 7.67(t, 1H), 7.34(d, 1H), 7.23-7.16(m, 3H), 3.22(s, 3H), 2.46(s, 3H) 491.1/490.1
70 CA Ν /=\ Ν-ΝΗΝ-4 Ν S^A2Aq Μ 0 ' '0 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(2- (methylsulfonyl)pyridin- 4-yl)-1 H-pyrazole-3- carboxyamide 9.30(s, 1H), 9.06(s, 1H), 8.66(d, 1H), 8.22(d, 1H), 8.17(d, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.70(t, 1H), 7.35(d, 1H), 7.24-7.20(m, 3H), 3.24(s, 3H), 2.43(s, 3H) 491.1/490.1
71 </Ν ^^ν-ν ην-Ζ f Ν 5-(benzo[i/]thiazol-6-yl)- N-(6-fluoropyridin-3- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide (300 MHz, DMSO-d6)<5 10.67(s, 1H), 9.45(s, 1H), 8.67(d, 1H), 8.38(1, 1H), 8.27(d, 1H), 8.03(d, 1H), 7.93(t, 1H), 7.57(d, 1H), 431.1/430.1
7.37-7.32(m, 2H), 7.26- 7.20(m, 2H), 2.25(s, 3H)
72 Αι ^Ν'ΝΗΝ-^ 'h 5-(benzo[i/]thiazol-6-yl)- N-(2-fluoropyridin-4- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3- carboxyamide 9.15(s, 1H), 9.06(s, 1H), 8.16(d, 1H), 8.07(d, 1H), 7.98(d, 1H), 7.67(t, 1H), 7.52(d, 1H), 7.34(d, 1H), 7.30(d, 1H), 7.23-7.16(m, 3H), 2.46(s, 3H) 431.1/430.1
73 A ^Ν-ΝΗΝ-ϋλο, €0^° 5-(benzo[i/]thiazol-6-yl)- N-(6-chloropyridin-3- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide 9.05(s, 1H), 8.92(s, 1H), 8.58(d, 1H), 8.36(dd, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.67(t, 1H), 7.35(d, 2H), 7.22-7.19(m, 3H), 2.44(s, 3H) 447.1/446.1
74 A 5-(benzo[i/]thiazol-6-yl)- N-(2-chloropyridin-4- yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3carboxyamide 9.09(s, 1H), 9.06(s, 1H), 8.31(d, 1H), 8.06(d, 1H), 7.98(d, 1H), 7.83(d, 1H), 7.67(t, 1H), 7.56(dd, 1H), 7.34(d, 1H), 7.23-7.16(m, 3H), 2.46(s, 3H) 447.1/446.1
75 A Μ Ν. Ν-Ν ΗΝ-^ <®ϊ^ι 0 5-(benzo[i/]thiazol-6-yl)- 1 -(6-methylpyridin-2- yl)-N-(thiazol-2-yl)-1H- 10.28(s, 1H), 9.05(s, 1H), 8.06(d, 1H), 8.00(d, 1H), 7.71(1, 1H), 7.51(d, 1H), 7.35(t, 2H), 7.21(s, 1H), 419.1/418.1
pyrazole-3carboxyamide 7.20(d, 1H), 7.03(d, 1H), 2.34(s, 3H)
76 A Ν-ΝΗΝ-^ 5-(benzo[i/]thiazol-6-yl)- N-benzyl-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.03(s, 1H), 8.04(d, 1H), 7.95(d, 1H), 7.61(1, 1H), 7.40-7.30(m, 7H), 4.67(d, 3H), 2.38(s, 3H) 426.1/425.1
77 5-(benzo[i/]thiazol-6-yl)- N-(2-fluorobenzyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.03(s, 1H), 8.03(d, 1H), 7.95(d, 1H), 7.63(1, 1H), 7.48-7.44(m, 2H), 7.34(dd, 1H), 7.20-7.09(m, 5H), 4.72(d, 2H), 2.38(s, 3H) 444.2/443.1
78 d Qto^ 5-(benzo[i/]thiazol-6-yl)- N-(3-fluorobenzyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.04(s, 1H), 8.04(d, 1H), 7.96(d, 1H), 7.62(1, 1H), 7.45(t, 1H), 7.35-7.30(m, 2H), 7.19-7.13(m, 5H), 6.97(1, 1H), 4.66(d, 2H), 2.39(s, 3H) 444.1/443.1
79 oF 5-(benzo[i/]thiazol-6-yl)- N-(4-fluorobenzyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.04(s, 1H), 8.04(d, 1H), 7.95(d, 1H), 7.61(1, 1H), 7.38-7.31(m, 4H), 7.177.13(m, 3H), 7.03(t, 2H), 4.63(d, 2H), 2.39(s, 3H) 444.1/443.1
80 0 O X ii *qz hn-Z'n 5-(benzo[d]thiazol-6-yl)- 1 -(6-methylpyridin-2yl)-N-(l- (methylsulfonyl)- 1Hpyrazol-4-yl)-lHpyrazole-3carboxyamide 9.06(s, 1H), 8.90(s, 1H), 8.61(s, 1H), 8.06(d, 1H), 7.99-7.97(m, 2H), 7.66(t, 1H), 7.35(d, 1H), 7.21- 7.14(m, 3H), 3.49(s, 3H), 2.46(s, 3H) 480.1/479.1
81 ( ,N o,,p HN-Z'N'SVy < Xj 0 5-(benzo[d]thiazol-6-yl)- N-(l- (cyclopropylsulfonyl)l/Z-pyrazol-4-yl)-1-(6methylpyridin-2-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.85(s, 1H), 8.58(s, 1H), 8.06(d, 1H), 7.97(m, 2H), 7.66(t, 1H), 7.36-7.33(m, 1H), 7.21- 7.16(m, 3H), 2.79-2.74(m, 1H), 2.45(s, 3H), 1.54- 1.49(m, 2H), 1.23-1.16(m, 2H) 506.1/505.1
[00470] [Example 82] 5-(Benzor<7]thiazol-6-yl)-A-(3-hydroxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide [00471] [00472]
Figure AU2017289021A1_D0038
1.
Figure AU2017289021A1_D0039
- (B enzo [</| thiazo 1- 6 - y 1) -2V- (3 - ((ter/butyldimethylsilyl)oxy)phenyl)-l-(6-methylpyridin-2-yl)-l//-pyrazole-3-carboxyamide [00473] A target compound (140 mg) was obtained in the same manner as in
Example 1 except that 3-((ieri-butyldimethylsilyl)oxy)aniline was used instead of panisidine.
[00474] Ή NMR spectrum (300 MHz, CDC13) δ 9.04(s, 1H), 8.79(s, 1H), 8.05(d,
1H), 7.97(d, 1H), 7.66(t, 1H), 7.40(d, 1H), 7.34(d, 1H), 7.26-7.17(m, 5H), 6.64-6.61(m, 1H), 2.43(s, 3H), 1.01(s, 9H), 0.25(S, 6H).
[00475] Step_______2._______5-(Benzor<7]thiazol-6-yl)-A-(3-hydroxyphenyl)-1-(6methv lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide [00476] After dissolving 5-(benzo[<7]thiazol-6-yl)-A-(3-((ieributyldimethylsilyl)oxy)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide (140 mg, 0.26 mmol) synthesized in Step 1 in tetrahydrofuran (2.5 mL), 1.0 M TBAF (0.78 mL, 0.78 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was removed under vacuum, and then ethyl acetate was added thereto. The organic layer was washed with sodium bicarbonate, and then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (23 mg).
[00477] Ή NMR spectrum (300 MHz, CDC13) δ 9.06(s, 1H), 8.93(s, 1H), 8.05(d, 1H), 8.00(d, 2H), 7.67(t, 1H), 7.38-7.18(m, 5H), 6.90(d, 1H), 6.68(d, 1H), 2.44(s, 3H). [00478] MS (ESI+): [M+H]+ m/z 428.1 [00479] [Examples 83 to 85] [00480] Compounds of Examples 83 to 85 listed in the following [Table 2] were obtained in the same manner as in Step 2) of Example 82.
[00481] [Table 2]
Example Number Structure Compound Name ’H NMR Spectrum (300 MHz, CDChk) MS (ES) Actual Measurement Value[M+H]+/
Required Value
83 A 5-(benzo[d]thiazol-6-yl)- N-(4-hydroxyphenyl)-1 (6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide 9.04(s, 1H), 8.71(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.66(t, 1H), 7.57(d, 2H), 7.37(d, 1H), 7.19(t, 3H), 6.85(d, 2H), 4.93(s, 1H), 2.44(s, 3H) 428.1/427.1
84 A HO 5-(benzo[d]thiazol-6-yl)- N-(3(hydroxymethyl)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.05(s, 1H), 8.89(s, 1H), 8.05(d, 1H), 7.99(d, 1H), 7.77(s, 1H), 7.67(t, 2H), 7.37(t, 2H), 7.26-7.14(m, 4H), 7.43(d, 2H), 2.43(s, 3H), 1.80(s, 1H) 442.1/441.1
85 a HnV ) , '' OH 0 5-(benzo[d]thiazol-6-yl)- N-(4(hydroxymethyl)phenyl) -1 -(6-methylpyridin-2yl)-1 H-pyrazole-3 carboxyamide 9.05(s, 1H), 8.88(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.73(d, 2H), 7.67(t, 1H), 7.36(td, 3H), 7.20(t, 3H), 4.69(d, 2H), 2.44(s, 3H) 442.1/441.1
[00482] [Example 86] N- (4-Aminophenyl) - 5 - (benzo [ d\ thiazo 1- 6- yl) -1-(6methy lp yridin- 2- yl) -1 H-y yrazo le- 3 -carboxy amide [00483] After dissolving 5 - (benzo [<i] thiazo 1-6-yl) -l-(6-methylpyridin-2-yl)-2V-(4nitrophenyl)-l/7-pyrazole-3-carboxyamide (65 mg, 0.14 mmol) synthesized in Example
14 in ethanol (1.5 mL) and dichloromethane (3mL), 20% PdOH/C (20 mg, 30% w/w) was added thereto at room temperature, and the reaction solution was stirred for 13 hours under hydrogen gas. The reaction solution was vacuum filtered through celite, and the solvent was vacuum concentrated. The result was purified using column chromatography to obtain a target compound (20 mg).
[00484] Ή NMR spectrum (300 MHz, CDC13) δ 9.09(s, 1H), 8.05(d, 1H), 8.00(d, 1H), 7.63(t, 1H), 7.52(d, 2H), 7.36(d, 1H), 7.21(d, 1H), 7.18(s, 1H), 7.05(d, 1H), 6.74(d, 2H), 3.38(s, 2H), 2.5l(s, 3H).
[00485] MS (ESI+): [M+H]+ m/z 427.1 [00486] [Example 87] 5 - (Benzo [d\ thiazo 1- 6- yl) -N- (4- (butylamino Iphenyl) -1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide
Figure AU2017289021A1_D0040
[00488] Step 1, 7eri-butyl(4-(5-(benzo[<7]thiazol-6-yr))-l-(6-methylpyridin-2-yl)177-pyrazole-3-carboxyamido)phenyl)(butyl)-carbamate [00489] A target compound (110 mg) was obtained in the same manner as in
Example 1 except that ieri-butyl(4-aminophenyl)(butyl)carbamate was used instead of panisidine.
[00490] Ή NMR spectrum (300 MHz, CDC13) δ 9.05(s, 1H), 8.85(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.71-7.64(m, 3H), 7.36(d, 1H), 7.20(td, 5H), 3.61(t, 2H), 2.44(s, 3H), 1.56-1.50(m, 2H), 1.43(s, 9H), 1.37-1.25(m, 2H), 0.90(t, 3H).
[00491] Step 2, 5-(Benzor<7]thiazol-6-yl)-A-(4-(butylamino)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide [00492] After dissolving ieri-butyl(4-(5-(benzo[<7]thiazo 1-6-yl))-1-(6methylpyridin-2-yl)-177-pyrazole-3-carboxyamido)phenyl)(butyl)-carbamate (110 mg,
0.19 mmol) synthesized in Step 1 in dichloromethane (1.5 mL), a 4.0 M hydrochloric acid
1,4-dioxane solution (0.28 mL, 1.13 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 13 hours at room temperature. After adding dichloromethane to the reaction solution, the organic layer was washed with sodium bicarbonate, dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (70 mg).
[00493] Ή NMR spectrum (300 MHz, CDC13) δ 9.05(s, 1H), 8.67(s, 1H), 8.06(d,
1H), 7.99(d, 1H), 7.67(t, 1H), 7.53(d, 2H), 7.36(d, 1H), 7.20(t, 3H), 6.64(d, 2H), 3.13(t, 10 2H), 2.44(s, 3H), 1.65-1.51(m, 2H), 1.51-1.41(m, 2H), 0.98(t, 3H).
[00494] MS (ESI+): [M+H]+ m/z 483.2 [00495] [Example 88] [00496] A compound of Example 88 listed in the following [Table 3] was obtained in the same manner as in Step 2) of Example 87.
[00497] [Table 31
Example Number Structure Compound Name ’H NMR Spectrum (300 MHz, CDCLk) MS (ES) Actual Measurement Value[M+H]+/ Required Value
88 A 5-(benzo[d]thiazol-6-yl)- N-(4- (cyclopropylamino)phen 9.04(s, 1H), 8.67(s, 1H), 8.05(d, 1H), 7.98(d, 1H), 7.66(t, 1H), 7.53(d, 2H), 467.2/466.2
yl)-1 -(6-methylpyridin- 2-yl)-1 H-pyrazole-3- carboxyamide 7.37(d, 1H), 7.36(t, 3H), 6.80(d, 2H), 2.46-2.43(m, 4H), 0.75-0.70(m, 2H), 0.54- 0.5 l(m, 2H)
[00498] [Example 89] 5 - (Benzo [ d\ thiazo 1- 6- yl) -1 - (6- methyip yridin- 2- y 1) -N- (4--( Smethylsulfonimidoyl)phenyl)-177-pyrazole-3-carboxyamide
Figure AU2017289021A1_D0041
[00500] Step 1, Ethyl-((4-(5-(benzor<7]thiazol-6-yl))-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamido)phenyl)(methyl)(oxo)-X6-sulfanylidine)carbamate [00501] A target compound (50 mg) was obtained in the same manner as in
Example 1 except that ethyl ((4-aminophenyl)(methyl)(oxo)-X6-sulfanylidine)carbamate was used instead of p-anisidine.
[00502] Ή NMR spectrum (300 MHz, CDC13) δ 9.16(s, 1H), 9.06(s, 1H), 8.06(d,
1H), 8.00-7.98(m, 5H), 7.67(t, 1H), 7.35(d, 1H), 7.23-7.17(m, 3H), 4.15-4.07(m, 2H), 3.33(s, 3H), 2.46(s, 3H), 1.24(t, 3H).
[00503] Step 2, 5-(Bcnzo|d|thiazol-6-yl)-l-(6-mcthylpyridin-2-yl)-Af-(4-(Smethylsulfonimidoyl)phenyl)-177-pyrazole-3-carboxyamide [00504] After dissolving ethyl-((4-(5-(benzo[<7]thiazo 1-6-yl))-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxyamido)phenyl)(methyl)(oxo)-X6-sulfanylidine)carbamate (50 mg, 0.09 mmol) synthesized in Step 1 in ethanol (1.0 mL), a 1.5 M sodium ethoxide ethanol solution (0.30 mL, 0.45 mmol) was added dropwise thereto at room temperature, and the reaction solution was stirred for 5 hours at 60°C. After adding saline to the reaction solution, the result was extracted using a mixed solution of dichloro methane and methanol.
The organic layer was dried using anhydrous magnesium sulfate, and after filtering, the filtrate was vacuum concentrated. The filtrate was purified using column chromatography to obtain a target compound (10 mg).
[00505] Ή NMR spectrum (300 MHz, CDC13) δ 9.16(s, 1H), 9.06(s, 1H), 8.087.92(m, 6H), 7.67(t, 1H), 7.35(d, 1H), 7.23-7.15(m, 3H), 3.13(t, 2H), 2.47(s, 3H).
[00506] MS (ESI+): [M+H]+ m/z 489.1 [00507] [Example 90] Preparation of 5-(ri,2,4]triazolori,5-«1pyridin-6-yl)-N-(2methoxyphenyl)-l-(6-methylpyridin-2-yl)-lH-pyrazole-3-carboxyamide [00508] Step 1, Preparation of 5-(ri,2,4]triazolori,5-«1pyridin-6-yl)-N-(4methoxyphenyl)-l-(6-methylpyridin-2-yl)-lH-pyrazole-3-carboxyamide [00509]
Figure AU2017289021A1_D0042
HATU, DIPEA
CH2CI2
Figure AU2017289021A1_D0043
[00510] After dissolving 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6methylpyridin-2-yl)-lH-pyrazole-3-carboxylic acid (30 mg, 0.09 mmol) synthesized in Step 4) of Preparation Example 2 in MAMimcthyl formamide (1 mL), HATU (42 mg, 0.11 mmol) and DIPEA (34 pL, 0.28 mmol) were introduced thereto, and the result was stirred for 30 minutes at room temperature. To the reaction solution, p-anisidine (11 pL, 0.09 mmol) was introduced, and the result was stirred for 12 hours at room temperature. The result was extracted with ethyl acetate, and the obtained organic layer was dried using anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and purified using column chromatography to obtain a target compound (20 mg, 50%).
[00511] Ή NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H),
7.96 (m, 1H), 7.83-7.72 (m, 3H), 7.54 (m, 1H), 7.32 (br, 2H), 6.96 (d, 2H), 3.76 (s, 3H),
2.17 (s, 3H).
[00512] MS (ESI+): m/z 426 [M+H]+.
[00513] [Examples 91 to 163] [00514] Compounds of Examples 91 to 163 listed in the following [Table 4] were obtained in the same manner as in Step 1) of Example 1 using various amine derivatives instead of p-anisidine.
[00515] [Table 4]
Example Structural Formula Compound Name Analysis Data
91 A >> N 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3methoxyphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.79 (brs, 1H), 8.72 (s, 1H), 8.38 (s, 1H), 7.76-7.69 (m, 2H), 7.57-7.47 (m, 3H), 7.27-7.15 (m, 4H), 6.72 (d, J = 8.1 Hz, 1H), 3.84 (s, 3H), 2.31 (s, 3H). MS (ESI+): m/z 426 [M+H]+.
92 cAi o' 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2methoxyphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 9.42 (brs, 1H), 8.73 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 7.80-7.64 (m, 3H), 7.49 (d, J = 9.0 Hz, 1H), 7.19 (s, 1H), 7.15-7.02 (m, 3H), 6.94 (d, J = 7.8 Hz, 1H), 3.95 (s, 3H), 2.26 (s, 3H). MS (ESI+): m/z 426 [M+H]+.
93 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4- hydroxyphenyl)-1-(6- Ή NMR (300 MHz, DMSO-d6) δ 10.0(s, 1H), 9.28(s, 1H), 9.18(s, 1H), 8.56(s, 1H), 7.98- 7.93(m, 1H), 7.79(m, 2H), 7.61-7.51(m, 3H),
methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide 7.32(d, 1H), 7.29(d, 1H), 6.77(d, 2H), 2.27(s, 3H). MS (ESI+): m/z 412 [M+H]+.
94 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4isopropylphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.71 (brs, 1H), 8.37 (s, 1H), 7.74-7.68 (m, 2H), 7.61-7.53 (m, 3H), 7.46 (d, J = 9.3 Hz, 1H), 7.18-7.13 (m, 2H), 6.90 (d, J = 8.1 Hz, 2H), 4.52 (q, J = 6.0 Hz, 1H), 2.29 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H). MS (ESI+): m/z 454 [M+H]+.
95 5-([l,2,4]triazolo[l,5a]pyridin-6-yl)-N-(4-(2methoxyethoxy)phenyl) -1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.71 (brs, 1H), 8.37 (s, 1H), 7.74-7.68 (m, 2H), 7.62 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.18-7.13 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 4.12 (t, J = 4.8 Hz, 2H), 3.75 (t, J = 4.8 Hz, 2H), 3.45 (s, 3H), 2.29 (s, 3H). MS (ESI+): m/z 454 [M+H]+.
96 Αι 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N(benzo[d] [1,3] dioxol-5 -yl) 1 -(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide Ή NMR (300 MHz, CDC13) δ 8.72 (brs, 1H), 8.39 (s, 1H), 7.76-7.69 (m, 2H), 7.56-7.44 (m, 3H), 7.19-7.15 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 5.98 (s, 2H), 2.31 (s, 3H). MS (ESI+): m/z 440 [M+H]+.
97 ^-n : «Aw ν-ν^^Λ ^=7 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2- fluoro-4-methoxyphenyl)-1 - Ή NMR (300 MHz, CDC13) δ 8.86 (brs, 1H), 8.73 (m, 1H), 8.39 (s, 1H), 8.31 (t, 1H), 7.80-7.69 (m, 2H), 7.63 (d, 1H), 7.48 (d, 1H), 7.19 (s, 1H), 7.15
(6-methylpyridin-2-yl)-1H- pyrazole-3-carboxyamide (d, 1H), 6.76-6.72 (m, 2H), 3.81 (s, 3H), 2.27 (s, 3H). MS (ESI+): m/z 444.2 [M+H]+
98 0 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3fluoro-4-methoxyphenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.72-8.70 (m, 2H), 8.39 (s, 1H), 7.76-7.70 (m, 2H), 7.63 (d, 1H), 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (d, 1H), 7.20-7.16 (m, 2H), 6.97 (t, 1H), 3.90 (s, 3H), 2.32 (s, 3H). MS (ESI+): m/z 444.2 [M+H]+
99 f3co „ SaMn^> 1 ° 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-1 -(6methylpyridin-2-yl)-N-(2(trifluoromethoxy)phenyl)- 1 //-pyrazolc-3- carboxyamide Ή NMR (300 MHz, CDC13) δ 9.33 (s, 1H), 8.75 (m, 1H), 8.60 (d, 1H), 8.39 (s, 1H), 7.79-7.68 (m, 3H), 7.50 (d, 1H), 7.40-7.32 (m, 2H), 7.18 (s, 2H), 7.13 (d, 1H), 2.23 (s, 3H). MS (ESI+): m/z 480.1 [M+H]+
100 u? O °9 Η<^ 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-1 -(6methylpyridin-2-yl)-N-(3(trifluoromethoxy)phenyl)- 1 //-pyrazolc-3carboxyamide Ή NMR (300 MHz, CDC13) δ 8.86 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 3H), 7.62 (d, 1H), 7.55 (d, 1H), 7.46 (d, 1H), 7.39 (t, 1H), 7.21 (s, 1H), 7.18 (d, 1H), 7.03(d, 1H), 2.32 (s, 3H). MS (ESI+): m/z 480.1 [M+H]+
101 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-1 -(6methylpyridin-2-yl)-N-(4(trifluoromethoxy)phenyl)- Ή NMR (300 MHz, CDC13) δ 8.86 (s, 1H), 8.73 (m, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 4H), 7.54 (d, 1H), 7.46 (d, 1H), 7.23-7.17 (m, 4H), 2.32 (s, 3H). MS (ESI+): m/z 480.1 [M+H]+
1 //-pyrazolc-3- carboxyamide
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.74 (s, 1H), 8.72
/ a]pyridin-6-yl)-N-(3- (m, 1H), 8.39 (s, 1H), 7.76-7.69 (m, 2H), 7.58 (d,
102 'ο (dimethylamino)phenyl)-1 - 1H), 7.46 (d, 1H), 7.31-7.15 (m, 4H), 6.96 (d,
(6-methylpyridin-2-yl)-1H- 1H), 6.55 (d, 1H), 2.99 (s, 6H), 2.31 (s, 3H). MS
pyrazole-3-carboxyamide (ESI+): m/z 439.2 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 9.91(s, 1H),
a]pyridin-6-yl)-N-(4- 9.18(s, 1H), 8.56(s, 1H), 7.97(t, 1H), 7.82-
103 ?-V!nOnh2 aminophenyl)-1 -(6- 7.79(m, 2H), 7.54(d, 1H), 7.45(d, 2H), 7.31(d,
methylpyridin-2-yl)-lH- 1H), 7.24(s, 1H), 6.54(d, 2H), 4.95(br, -NH2),
pyrazole-3-carboxyamide 2.16(s, 3H) MS (ESI+): m/z 411 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 9.99(s, 1H),
/ a]pyridin-6-yl)-N-(4- 9.17(s, 1H), 8.55(s, 1H), 7.95(m, 1H), 7.95-
104 rVT-O-N' ν-ν^ΑΛ^0 χ (dimethylamino)phenyl)-1 - 7.93(m, 2H), 7.78(d, 2H), 7.53(d, 1H), 7.30-
(6-methylpyridin-2-yl)-1 -H- 7.25(m, 2H), 6.72(d, 2H), 2.87(s, 6H), 2.16(s,
pyrazole-3-carboxyamide 3H). MS (ESI+): m/z 439 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.72 (s, 1H), 8.60
/ a]pyridin-6-yl)-/V-(4- (s, 1H), 8.38 (s, 1H), 7.75-7.69 (m, 2H), 7.58-7.53
ά (pyrrolidin-1 -yl)phenyl) 1 -
105 Ν Σϋ4ΝθΌ (m, 3H), 7.47 (d, 1H), 7.19 (s, 1H), 7.15 (d, 1H),
(6-methylpyridin-2-yl)- - 6.57 (d, 2H), 3.32-3.27(m, 4H), 2.30 (s, 3H),
1 //-pyrazolc-3- 2.03-1.99 (m, 4H). MS (ESI+): m/z 465.2 [M+H]+
carboxyamide
5-([1,2,4]triazolo[l ,5- Ή NMR (300 MHz, CDC13) δ 8.71 (brs, 1H), 8.64
a]pyridin-6-yl)-N-(4-((2- (s, 1H), 7.78-7.69 (m, 2H), 7.57-7.55 (m, 3H),
106 ό (dimethylamino)ethyl)(met 7.46 (d, J = 9.3 Hz, 1H), 7.19-7.14 (m, 2H), 6.74
hyl)amino)phenyl)-1 -(6- (d, J = 9.0 Hz, 2H), 3.51 (t, J = 7.5 Hz, 2H), 3.96
methylpyridin-2-yl)-lH- (s, 3H), 2.57 (t, J = 7.2 Hz, 2H), 2.36 (s, 6H), 2.30
pyrazole-3-carboxyamide (s, 3H). MS (ESI+): m/z 496 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.72 (s, 1H), 8.70
a]pyridin-6-yl)-N-(4-(4- (s, 1H), 8.38 (s, 1H), 7.77-7.69 (m, 2H), 7.62-7.54
ό methylpiperazin-1 -
107 (m, 3H), 7.47 (d, 1H), 7.19-7.14 (m, 2H), 6.95 (d,
° yl)phenyl)-1-(6- 2H), 3.21 (m, 4H), 2.60 (m, 4H), 2.36 (s, 3H),
methylpyridin-2-yl)-lH- 2.31 (s, 3H). MS (ESI+): m/z 494.2 [M+H]+
pyrazole-3-carboxyamide
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.72 (s, 1H), 8.70
a]pyridin-6-yl)-N-(4-(4- (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 2H), 7.63 (d,
νΑμν-<><η° acetylpiperazin-1 - 2H), 7.55 (d, 1H), 7.47 (d, 1H), 7.20-7.15 (m,
108
yl)phenyl)-1-(6- 2H), 6.95 (d, 2H), 3.80-3.77 (m, 2H), 3.65-3.62
methylpyridin-2-yl)-lH- (m, 2H), 3.19-3.12 (m, 4H), 2.31 (s, 3H), 2.15 (s,
pyrazole-3-carboxyamide 3H). MS (ESI+): m/z 522.2 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.72 (brs, 1H), 8.66
a]pyridin-6-yl)-N-(4-((l, 1 - (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 2H), 7.58-7.54
109 ^'Mn~O-nh dioxidotetrahydrothiophen- (m, 3H), 7.46 (d, J = 9.0 Hz, 1H), 7.19-7.15 (m,
0 3-yl)amino)phenyl)-1-(6- 2H), 6.66 (d, J = 9.0 Hz, 2H), 4.41-4.36 (m, 1H),
methylpyridin-2-yl)-lH- 4.01-3.98 (m, 1H), 3.76-3.69 (m, 1H), 3.303.28
pyrazole-3-carboxyamide (m, 1H), 3.04-3.00 (m, 1H), 2.70-2.50 (m, 1H),
2.36-2.31 (m, 1H), 2.31 (s, 3H). MS (ESI+): m/z 496 [M+H]+.
110 ^'V1N~O-NH 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4- acetamidophenyl)-1 -(6- methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.22 (brs, 1H), 9.93 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.84-7.73 (m, 4H), 7.57-7.50 (m, 3H), 7.32-7.29 (m, 2H), 2.17 (s, 3H), 2.03 (s, 3H). MS (ESI+): m/z 453 [M+H]+.
111 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4((dimethylamino)methyl)ph enyl)-1 -(6-methylpyridin-2- yl)-1 H-pyrazole-3 carboxyamide Ή NMR (300 MHz, CDC13) δ 8.82 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.79-7.69 (m, 4H), 7.56 (d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.21 (s, 1H), 7.17 (d, 1H), 3.50 (s, 2H), 2.31 (s, 9H). MS (ESI+): m/z 453.2 [M+H]+
112 J UN- η 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2(methylcarbamoyl)phenyl)1 -(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 12.66 (brs, 1H), 9.21 (s, 1H), 8.77 (brs, 1H), 8.65 (d, J = 8.1 Hz, 1H), 8.57 (s, 1H), 8.01 (t, J = 8.1 Hz, 1H), 7.837.77 (m, 3H), 7.59-7.53 (m, 2H), 7.34-7.31 (m, 2H), 7.23-7.18 (m, 1H), 2.83 (s, 3H), 2.15 (s, 3H). MS (ESI+): m/z 453 [M+H]+.
113 1 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4(methylcarbamoyl)phenyl)1 -(6-methylpyridin-2-yl)- Ή NMR (300 MHz, DMSO-d6) δ 10.46 (brs, 1H), 9.18 (s, 1H), 8.55 (s, 1H), 8.35 (brs, 1H), 7.98- 7.91 (m, 3H), 7.84-7.78 (m, 4H), 7.51 (d, J = 9.3 Hz, 1H), 7.32-7.29 (m, 2H), 2.77 (s, 3H), 2.16 (s, 3H). MS (ESI+): m/z 453 [M+H]+.
lH-pyrazole-3- carboxyamide
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 10.29(s, 1H),
A a]pyridin-6-yl)-1 -(6- 9.20(s, 1H), 8.57(s, 1H), 7.95(t, 1H), 7.86-
114 ^A-n n-n^A/ -TO methylpyridin-2-yl)-N- 7.80(m, 4H), 7.54(d, 1H), 7.40-7.31(m, 4H),
phenyl-1 //-pyrazolc-3- 7.12(t, 1H), 2.18(s, 3H). MS (ESI+): m/z 396
carboxyamide [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.ΊΊ (s, 1H), 8.73
A a]pyridin-6-yl)-1 -(6- (s, 1H), 8.48 (m, 1H), 8.39 (s, 1H), 8.14-8.11 (m,
115 Aj-N n-n^A/ -4nA methylpyridin-2-yl)-N-(o- 3H), 7.77-7.70 (m, 2H), 7.61 (d, 1H), 7.56 (d,
Ν^Αίί^ tolyl) -177-pyr azole-3 - 1H), 7.23-7.14 (m, 2H), 2.40 (s, 3H), 2.27 (s, 3H).
carboxyamide MS (ESI+): m/z 410.2 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.74 (s, 1H), 8.73
A a]pyridin-6-yl)-1 -(6- (s, 1H), 8.39 (s, 1H), 7.76-7.69 (m, 2H), 7.59-7.45
116 A-N n-n^A/ jn~(5 methylpyridin-2-yl)-N-(m- (m, 4H), 7.29-7.25 (m, 1H), 7.20 (s, 1H), 7.16 (d,
tolyl) -177-pyr azole-3 - 1H), 6.99 (s, 1H), 2.39 (s, 3H), 2.30 (s, 3H). MS
carboxyamide (ESI+): m/z 410.2 [M+H]+
117 A. ν-ν^ΑΛ VAA rO- 0 5-([l,2,4]triazolo[l,5a]pyridin-6-yl)-1 -(6methylpyridin-2-yl)-N-(ptolyl) -177-pyr azole-3 carboxyamide Ή NMR (300 MHz, CDC13) δ 8.72 (s, 2H), 8.38 (s, 1H), 7.78-7.69 (m, 2H), 7.61-7.55 (m, 3H), 7.46 (dd, 1H), 7.19-7.14 (m, 4H), 2.34 (s, 3H), 2.30 (s, 3H). MS (ESI+): m/z 410.2 [M+H]+
118 A rV^ ν*ΑΑ CF3 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-1 -(6- Ή NMR (300 MHz, CDC13) δ 8.91 (s, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.00-7.96 (m, 2H), 7.78-7.70
methylpyridin-2-yl)-N-(3- (trifluoromethyl)phenyl)- 1 //-pyrazolc-3- carboxyamide (m, 2H), 7.58-7.40 (m, 4H), 7.21 (s, 1H), 7.18 (d, 1H), 2.32 (s, 3H). MS (ESI+): m/z 464.1 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.80 (s, 1H), 8.73
1 a]pyridin-6-yl)-1 -(6- (s, 1H), 8.39 (s, 1H), 7.80-7.70 (m, 4H), 7.61-7.56
119 ν-ν^ΑΛ^0 methylpyridin-2-yl)-N-(4- (m, 2H), 7.46 (d, 1H), 7.34 (t, 1H), 7.22-7.15 (m,
vinylphenyl)-1 //-pyr azole- 2H), 6.73 (dd, 1H), 5.80 (d, 1H), 5.29 (d, 1H),
3-carboxyamide 2.31 (s, 3H). MS (ESI+): m/z 422.2 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.90 (s, 1H), 8.73
I a]pyridin-6-yl)-N-(3- (s, 1H), 8.40 (s, 1H), 8.12 (m, 1H), 7.95 (d, 1H),
120 Aw-cT cyanophenyl)-1 -(6- 7.78-7.71 (m, 2H), 7.55-7.44 (m, 4H), 7.22 (s,
methylpyridin-2-yl)-lH- 1H), 7.20 (d, 1H), 2.33 (s, 3H). MS (ESI+): m/z
pyrazole-3-carboxyamide 421.1 [M+H]+
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMS0-d6) δ 10.70(s, 1H),
I a]pyridin-6-yl)-N-(4- 9.18(s, 1H), 8.55(s, 1H), 8.08-8.05(m, 2H), 7.95-
121 i'»4(n^O-cn cyanophenyl)-1 -(6- 7.92(m, 2H), 7.84-7.78(m, 3H), 7.52(d, 1H),
methylpyridin-2-yl)-1 -H- 7.35-7.30(m, 2H), 2.25(s, 3H). MS (ESI+): m/z
pyrazole-3-carboxyamide 421 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMS0-d6) δ 10.50(s, 1H),
Λ ο a]pyridin-6-yl)-N-(3- 9.18(s, 1H), 8.55(s, 1H), 8.43(s, 1H), 8.12(d, 1H),
122 acetylphenyl)-1 -(6- 7.98-7.93(m,lH), 7.84-7.73(m,2H), 7.73(d, 1H),
methylpyridin-2-yl)-lH- 7.70-7.52(m, 2H), 7.32(br,2H), 2.58(s, 3H),
pyrazole-3-carboxyamide 2.16(s, 3H). MS (ESI+): m/z 438 [M+H]+.
123 '-z λ 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4acetylphenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.59(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.99-7.95(m, 5H), 7.837.78(m,2H), 7.53(d, 1H), 7.34(br,2H), 2.54(s, 3H), 2.25(s, 3H). MS (ESI+): m/z 438 [M+H]+.
124 IL-^^ Z ?7 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2fluorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.0(s, 1H), 9.20(s, 1H), 8.57(s, 1H), 7.96(t, 1H), 7.837.78(m, 3H), 7.54(d, lH),7.33-7.25(m, 5H),2.18(s, 3H). MS (ESI+): m/z 414 [M+H]+.
125 η 5^34O 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3fluorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.48(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.98(1, 1H), 7.817.78(m, 3H), 7.66(d, 1H), 7.52(d, 1H), 7.486.97(m, 3H), 6.91(1, 1H), 2.18(s, 3H). MS (ESI+): m/z 414 [M+H]+.
126 <TT^ 0 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4fluorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.37(s, 1H), 9.17(s, 1H), 8.56(s, 1H), 7.98-7.79(m, 5H), 7.52(d, 1H), 7.31-7.17(m, 4H), 2.25(s, 3H). MS (ESI+): m/z 414 [M+H]+.
127 /*% Cl x JlV?~0 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2- chlorophenyl)-1-(6- Ή NMR (300 MHz, DMSO-d6) δ 10.00(s, 1H), 9.34(s, 1H), 8.57(s, 1H), 7.97(m, 2H), 7.80(m, 2H), 7.58(m, 3H), 7.42-7.35(m, 3H), 2.17(s, 3H). MS (ESI+): m/z 430 [M+H]+.
methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide
128 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3chlorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.45(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 8.16(s, 1H), 7.98(1, 1H), 7.86-7.79(m, 3H), 7.50(d, 1H), 7.32(br, 4H), 2.17(s, 3H). MS (ESI+): m/z 430 [M+H]+.
129 ^S'N>JlN-O-ci 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4chlorophenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.45(s, 1H), 9.19(s, 1H), 8.57(s, 1H), 7.99-7.80(m, 5H), 7.53(d, 1H), 7.44(m, 2H), 7.31(br, 2H), 2.25(s, 3H). MS (ESI+): m/z 430 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 9.87(s, 1H),
Br a]pyridin-6-yl)-N-(2- 9.18(s, 1H), 8.56(s, 1H), 7.96-7.93(m, 2H), 7.82-
130 bromophenyl)-1 -(6- 7.74(m, 2H), 7.54-7.43(m, 3H), 7.33(br, 2H),
methylpyridin-2-yl)-lH- 7.16(t, 1H), 2.16(s, 3H). MS (ESI+): m/z 474
pyrazole-3-carboxyamide [M+H]+.
131 ν 0 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3- bromophenyl)-1 -(6- methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.45(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 8.16(s, 1H), 7.98(1, 1H), 7.86-7.79(m, 3H), 7.50(d, 1H), 7.32(br, 4H), 2.17(s, 3H). MS (ESI+): m/z 474 [M+H]+.
132 Γ^Ν 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4- Ή NMR (300 MHz, DMSO-d6) δ 10.44(s, 1H), 9.19(s, 1H), 8.57(s, 1H), 7.99(1, 1H), 7.86-
bromophenyl)-1 -(6- methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide 7.79(m, 2H), 7.57-7.50(m, 4H), 7.31(br, 3H), 2.25(s, 3H). MS (ESI+): m/z 474 [M+H]+.
133 Ν 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2,3difluorophenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.27(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.97(t, 1H), 7.78(t, 2H), 7.48(d, 2H), 7.31-7.21(m, 4H), 2.16(s, 3H). MS (ESI+): m/z 432 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 10.08(s, 1H),
a]pyridin-6-yl)-N-(2,4- 9.18(s, 1H), 8.55(s, 1H), 7.97(t, 1H), 7.78(t, 2H),
134 '-z difluorophenyl)-1 -(6- 7.68-7.66(m, 1H), 7.52(d, 1H), 7.37-7.29(m, 3H),
methylpyridin-2-yl)-lH- 7.13(t, 1H), 2.06(s, 3H). MS (ESI+): m/z 432
pyrazole-3-carboxyamide [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 10.04(s, 1H),
fl\| E a]pyridin-6-yl)-N-(2,5- 9.18(s, 1H), 8.55(s, 1H), 7.95(1, 1H), 7.81-
135 5l54n~0 difluorophenyl)-1 -(6- 7.71(m, 3H), 7.52(d, 1H), 7.41-7.33(br, 3H),
methylpyridin-2-yl)-lH- 7.13-7.09(m, 1H), 2.17(s, 3H). MS (ESI+): m/z
pyrazole-3-carboxyamide 432 [M+H]+.
136 u_ 7φ ^r° <> 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3,4difluorophenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.64(s, 1H), 9.20(s, 1H), 8.55(s, 1H), 7.95(1, 2H), 7.65(br, 2H), 7.49(br, 1H), 7.49-7.39(m, 2H), 7.32(br, 2H), 2.25(s, 3H). MS (ESI+): m/z 432 [M+H]+.
137 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3,5difluorophenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDCh) δ 9.19(s, 1H), 8.98(s, 1H), 8.24(s, 1H), 7.80-7.73(m, 2H), 7.70-7.60(m, 3H, 7.55-7.44(m, 3H), 6.64-6.57(m, 1H), 2.25(s, 3H). MS (ESI+): m/z 432 [M+H]+.
138 <° 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3chloro-2-fluorophenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.24(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.94(t, 2H), 7.78(t, 2H), 7.66(m, 1H), 7.51-7.43(m, 2H), 7.31-7.25(m, 3H), 2.16(s, 3H). MS (ESI+): m/z 448 [M+H]+.
139 CC; b 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4chloro-2-fluorophenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.33(s, 1H), 9.44(s, 1H), 8.56(s, 1H), 7.83(1, 1H), 7.797.73(m, 3H), 7.65-7.50(m, 3H), 7.32(br, 2H), 2.18(s, 3H). MS (ESI+): m/z 448 [M+H]+.
140 ό /4' iN'N^N~O-f z,n-nV^o VO 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3chloro-4-fluorophenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.52(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 8.12(d, 2H), 7.95(1, 1H), 7.80-7.78(br, 2H), 7.52-7.40(m, 2H), 7.32(br, 2H), 2.17(s, 3H). MS (ESI+): m/z 448 [M+H]+.
141 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3,4- dichlorophenyl)-1-(6- Ή NMR (300 MHz, DMSO-d6) δ 10.59(s, 1H), 9.18(s, 1H), 8.55(s, 1H), 7.98(s, 1H), 7.987.78(m, 4H), 7.64(d, 1H), 7.61(d, 1H), 7.21(br, 2H), 2.17(s, 3H). MS (ESI+): m/z 464 [M+H]+.
methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide
142 fAl Br 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(2bromo-4-fluorophenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, DMS0-d6) δ 10.17(s, 1H), 9.14(s, 1H), 8.49(s, 1H), 7.96(1, 1H), 7.857.70(m, 4H), 7.51(m, 1H), 7.32(br, 3H), 2.17(s, 3H). MS (ESI+): m/z 492 [M+H]+.
143 η 1 0 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3(methoxythio)phenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.80 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.76-7.70 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.19-7.15 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 2.52 (s, 3H), 2.19 (s, 3H). MS (ESI+): m/z 442 [M+H]+.
144 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4(methoxythio)phenyl)-1 -(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.ΊΊ (brs, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 7.77-7.66 (m, 4H), 7.56 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.32- 7.29 (m, 2H), 7.18-7.16 (m, 2H), 2.50 (s, 3H), 2.32 (s, 3H). MS (ESI+): m/z 442 [M+H]+.
145 0&~ ^Ή-ΝΗΙ'Ι-Ζ'^ 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(3(methylsulfinyl)phenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 9.03 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 8.01-7.98 (m, 2H), 7.78-7.70 (m, 2H), 7.60-7.37 (m, 4H), 7.20-7.16 (m, 2H), 2.77 (s, 3H), 2.30 (s, 3H). MS (ESI+): m/z 458 [M+H]+.
146 n-nV^ ό 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4(methylsulfinyl)phenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.98 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.79-7.66 (m, 4H), 7.55 (d, J= 7.8 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.21-7.17 (m, 2H), 2.74 (s, 3H), 2.32 (s, 3H). MS (ESI+): m/z 458 [M+H]+.
147 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4(methylsulfonyl)phenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 9.06 (brs, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 7.97 (m, 4H), 7.82-7.72 (m, 2H), 7.55 (d, J= 8.1 Hz, 1H), 7.48 (d, J = 9.3 Hz, 1H), 7.24-7.20 (m, 2H), 3.09 (s, 3H), 2.35 (s, 3H). MS (ESI+): m/z 474 [M+H]+.
148 A J''lV5N~O-?-NH2 «ρΑ^, ' ό 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4sulfomoylphenyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.63 (brs, 1H), 9.21 (s, 1H), 8.57 (s, 1H), 8.04-7.94 (m, 3H), 7.83-7.80 (m, 4H), 7.53 (d, J = 9.3 Hz, 1H), 7.35- 7.30 (m, 4H), 2.19 (s, 3H). MS (ESI+): m/z 475 [M+H]+.
149 ArvrO-S1 ν.ν^ΑΛ^ 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4-(Smethylsulfonimidoyl)pheny 1)-1 -(6-methylpyridin-2-yl)lH-pyrazole-3carboxyamide Ή NMR (300 MHz, CDC13) δ 9.05 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.04-7.91 (m, 4H), 7.77-7.70 (m, 2H), 7.53 (d, J= 7.8 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.22-7.18 (m, 2H), 3.12 (s, 3H), 2.33 (s, 3H). MS (ESI+): m/z 473 [M+H]+.
150 A ό λ- 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4- (propylsulfonyl)phenyl)-1 - Ή NMR (300 MHz, CDC13) δ 9.06 (brs, 1H), 8.75 (s, 1H), 8.41 (d, J = 6.9 Hz, 2H), 7.80-7.48 (m, 4H), 7.24-7.20 (m, 2H), 7.07 (d, J = 7.2 Hz, 1H),
100
(6-methylpyridin-2-yl)-1H- pyrazole-3-carboxyamide 6.84 (s, 1H), 3.12-3.07 (m, 1H), 2.20 (s, 3H), 1.81-1.71 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). MS (ESI+): m/z 502 [M+H]+.
151 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(4(propylsulfonyl)phenyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 9.04 (brs, 1H), 8.73 (s, 1H), 8.39 (s, 1H), 7.95-7.88 (m, 4H), 7.80-7.70 (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H), 7.43-7.18 (m, 2H), 2.50-2.44 (m, 1H), 2.33 (s, 3H), 1.38-1.32 (m, 2H), 1.07-1.00 (m, 3H). MS (ESI+): m/z 502 [M+H]+.
152 CO^^0 N 5-([l,2,4]triazolo[[l,5- a]pyridin-6-yl)-N-(6fluoropyridin-3-yl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 10.68 (brs, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.40 (t, J = 6.9 Hz, 1H), 7.97 (t, J = 7.8 Hz, 1H), 7.83-7.78 (m, 2H), 7.51 (d, J= 9.3 Hz, 1H), 7.35-7.33 (m, 2H), 7.24 (d, J = 8.7 Hz, 1H), 2.20 (s, 3H). MS (ESI+): m/z 415 [M+H]+.
153 ^φ-οι N-N-^fa VN 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(6chloropyridin-3-yl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 9.42(s, 1H), 8.74(s, 1H), 8.49(br, 2H), 7.91(t, 1H), 7.75(d, 1H), 7.64(d, 2H), 7.50-7.48(m, 2H), 7.37(d, 1H), 7.27(s, 1H), 2.13(s, 3H). MS (ESI+): m/z 431 [M+H]+.
154 ( /N n-nV*24 Vn 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(6- methoxypyridin-3-yl)-1-(6- Ή NMR (300 MHz, CDC13) δ 8.72 (brs, 1H), 8.71 (s, 1H), 8.68-8.36 (m, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.76-7.69 (m, 2H), 7.54 (d, J = 7.8 Hz, 1H0, 7.45 (d, J = 9.0 Hz, 1H), 7.24-7.15 (m, 2H), 6.79
101
methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide (d, J = 9.0 Hz, 1H), 3.94 (s, 3H), 2.32 (s, 3H). MS (ESH): m/z 427 [M+H]+.
5-([1,2,4]triazolo[l ,5- Ή NMR (300 MHz, DMSO-d6) δ 9.25(s, 1H),
J /-. a]pyridin-6-yl)-N-(2- 9.01(t, 1H), 8.54(s, 1H), 7.89(t, 1H), 7.77(d, 1H),
155 Α,νην-Η fluorobenzyl)-1 -(6- 7.70(d, 1H), 7.51(d, 1H), 7.38-7.27(m, 3H),
methylpyridin-2-yl)-lH- 7.14(br, 2H), 4.54(d, 2H), 2.15(s, 3H). MS (ESH):
pyrazole-3-carboxyamide m/z 428 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 9.15(s, 1H),
/ a]pyridin-6-yl)-N-(3- 9.00(t, 1H), 7.95(s, 1H), 7.81(t, 1H), 7.78(d, 1H),
156 ά Ρ-= n~n^/V7 fluorobenzyl)-1 -(6- 7.71(d, 1H), 7.52(d, 1H), 7.48-7.28(m, 3H),
methylpyridin-2-yl)-lH- 7.15(br, 2H), 4.55(d, 2H), 2.15(s, 3H). MS (ESH):
pyrazole-3-carboxyamide m/z 428 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, DMSO-d6) δ 9.21(s, 1H),
/ / a]pyridin-6-yl)-N-(4- 9.10(t, 1H), 8.61(s, 1H), 7.87(t, 1H), 7.83(d, 1H),
ά 0
157 ^^ν-νην-/ fluorobenzyl)-1 -(6- 7.75(d, 1H), 7.57(d, 1H), 7.46-7.42(m, 2H),
methylpyridin-2-yl)-lH- 7.33(d, 1H), 7.18(br, 3H), 4.53(d, 2H), 2.22(s,
pyrazole-3-carboxyamide 3H). MS (ESH): m/z 428 [M+H]+.
5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.71 (brs, 1H), 8.39
a]pyridin-6-yl)-N-(3- (s, 1H), 7.72-7.69 (m, 2H), 7.52-7.45 (m, 2H),
ό Ρ-°ζ
158 ^^ν-Νην-/ methoxybenzyl)-1-(6- 7.31-7.11 (m, 3H), 6.99-6.87 (m, 3H), 4.66 (d, J =
methylpyridin-2-yl)-lH- 4.0 Hz, 2H), 3.82 (s, 3H), 2.28 (s, 3H). MS (ESH):
pyrazole-3-carboxyamide m/z 440 [M+H]+.
159 5-([l,2,4]triazolo[l,5- Ή NMR (300 MHz, CDC13) δ 8.71 (brs, 1H), 8.39
N-n^^=O> a]pyridin-6-yl)-N-(4- (s, 1H), 7.72-7.68 (m, 2H), 7.51-7.44 (m, 2H),
102
methoxybenzyl)-1-(6- methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide 7.33 (d, J = 8.7 Hz, 2H), 7.15-7.11 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 4.0 Hz, 2H), 3.82 (s, 3H), 2.28 (s, 3H). MS (ESI+): m/z 440 [M+H]+.
160 5-([1,2,4]triazolo[l ,5a]pyridin-6-yl)-N-(4(dimethylamino)benzyl)-1 (6-methylpyridin-2-yl)-1Hpyrazole-3-carboxyamide Ή NMR (300 MHz, CDC13) δ 8.70 (s, 1H), 8.37 (s, 1H), 7.70-7.66 (m, 2H), 7.47 (dd, 2H), 7.287.25 (m, 3H), 7.13 (s, 1H), 7.10 (d, 1H), 6.73 (d, 2H), 4.57 (d, 2H), 2.94 (s, 6H), 2.25 (s, 3H). MS (ESI+): m/z 453.2 [M+H]+
161 λ {χΥ^° 5-([l,2,4]triazolo[l,5- a]pyridin-6-yl)-N-(acetamidobenzyl)-1-(6methylpyridin-2-yl)-lHpyrazole-3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 8.90 (brs, 1H), 9.15 (s, 1H), 8.99 (t, 1H), 8.55 (s, 1H), 7.91 (t, J = 8.1 Hz, 1H), 7.80 (d, J = 9.3 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.53-7.47 (m, 3H), 7.29-7.24 (m, 3H), 7.18 (s, 1H), 4.42 (d, J = 4.0 Hz, 2H), 2.15 (s, 3H), 2.01 (s, 3H). MS (ESI+): m/z 467 [M+H]+.
162 /Ν ο,,ο ^%-Ν ΗΝ-Λ-Ν'^ μ A.JM. Ν=ν ° 5-([ 1,2,4]triazolo[ 1,5a]pyridin-6-yl)-1 -(6methylpyridin-2-yl)-N-( 1 (methylsulfonyl)- 1Hpyrazol-4-yl)-lH-pyrazole3-carboxyamide Ή NMR (300 MHz, DMSO-d6) δ 8.76(s, 1H), 8.73(s, 1H), 8.62(s, 1H), 8.39(s, 1H), 8.01(s, 1H), 7.79-7,70(m, 2H), 7.53(d, 1H), 7.45(d, 1H), 7.20- 7.17(m, 2H), 3.33(s, 3H), 2.33(s, 3H). MS (ESI+): m/z 464.1 [M+H]+.
163 ( ,Ν ο,,ο ^Λ'Ν HN-Z'N'S^y Μ Χ.>~< Ν=Ν ν 5-([ 1,2,4]triazolo[ 1,5a]pyridin-6-yl)-N-( 1 cyclopropylsulfonyl) -1Hpyrazol-4-yl)-1-(6- Ή NMR (300 MHz, DMSO-d6) δ 8.78(s, 1H), 8.73(s, 1H), 8.59(s, 1H), 8.40(s, 1H), 7.99(s, 1H), 7.79-7.71(m, 2H), 7.53(d, 1H), 7.45(d, 1H), 7.20- 7.17(m, 2H), 2.80-2.75(m, 1H), 2.33(s, 3H), 1.57-
103
methylpyridin-2-yl)-lH- pyrazole-3-carboxyamide 1.50(m, 2H), 1.19-1.14(m, 2H). MS (ESI+): m/z 506.1 [M+H]+.
[00526] [Example 164] Preparation of A-(4-methoxyphenyl)-l-(6-methylpyridin2-yl)-5-(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide
Figure AU2017289021A1_D0044
[00528]
After dissolving Intermediate 3 (50 mg, 0.15 mmol) in N,Ndimethylformamide, HATU (69 mg, 0.18 mmol) and DIPEA (79 pL, 0.45 mmol) were introduced thereto, and the result was stirred for 30 minutes at room temperature. To the reaction solution, p-anisidine (20 mg, 0.17 mmol) was introduced, and the result was stirred for 12 hours at room temperature. Produced solids were filtered, washed with ethyl acetate, and then vacuum dried to obtain a target compound (42 mg).
[00529] Ή NMR spectrum (300 MHz, DMSO-d6) δ 10. l(s, 1H), 8.96(s, 2H), 8.077.93(m, 3H), 7.78-7.73(m, 4H), 7.37(br, 2H), 6.92(d, 2H), 3.75(s, 3H), 2.17(s, 3H).
[00530] MS (ESI+): [M+H] + m/z 437.1 [00531] [Examples 165 to 201] [00532] Compounds of Examples 161 to 198 listed in the following [Table 5] were obtained in the same manner as in Example 160 using various amine derivatives instead of p-anisidinc.
[00533] [Table 51
104
Example Number Structure Compound Name ’H NMR Spectrum (300 MHz, CDChk) MS (ES) Actual Measurement Value[M+H]+/ Required Value
165 /A o N-(3-methoxyphenyl)-1 - (6-methylpyridin-2-yl)- 5-(quinoxalin-6-yl)-1Hpyrazole-3carboxyamide 10.2(s, 1H), 8.96(s, 2H), 8.07-8.03(m, 2H), 7.96(t, 1H), 7.75(t, 2H), 7.53- 7.46(m, 2H), 7.40-7.34(m, 2H), 7.26(t, 1H), 6.69(d, 1H), 3.76(s, 3H), 2.17(s, 3H) 437.1/436.1
166 fAl OZ N-(2-methoxyphenyl)-1 - (6-methylpyridin-2-yl)- 5-(quinoxalin-6-yl)-1Hpyrazole-3carboxyamide 9.43(s, 1H), 8.97(s, 2H), 8.28(d, 1H), 8.07-7.95(m, 3H), 7.78(dd, 2H), 7.43(s, 1H), 7.39(d, 1H), 7.15(br, 2H), 7.13(m, 1H), 3.91(s, 3H), 2.19(s, 3H) 437.1/436.1
167 Ai ^A|-N NH-Z \ 0 Λ/ S Γ Yj^ ° 0 #-(4-(2- mcthox yet hox y) phen y 1) - 1 -(6-methylpyridin-2yl)-5-(quinoxalin-6-yl)lH-pyrazole-3carboxyamide 8.87(s, 2H), 8.78(s, 1H), 8.09-8.03(m, 2H), 7.70- 7.63(m, 4H), 7.37(d, 1H), 7.29(s, 1H), 7.17(d, 1H), 6.95(d, 2H), 4.14(q, 2H), 481.2/480.2
105
3.76(q, 2H), 3.46(s, 3H), 2.34(s, 3H)
168 ά Ν-Ν ην-4 \-0 χ/ Γ Η Ί 0 AHbcn ζο| <71 [ 1,3 ] dioxol- 5-yl)-l-(6- methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 10.19(s, 1H), 8.95(s, 2H), 8.06-8.00(m, 2H), 7.94(t, 1H), 7.76-7.68(m, 2H), 7.48(d, 1H), 6.89(d, 1H), 5.99(s, 2H), 2.16(s, 3H) 450.1/451.1
169 NJjty<NM^ Γ ΊΓί^ ° /V-(2,3dihydrobenzofZ?] [1,4]dio xin-6-yl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.87(s, 2H), 8.71(s, 1H), 8.08-8.03(m, 2H), 7.70- 7.64(m, 2H), 7.39-7.36(m, 2H), 7.29(s, 1H), 7.18- 7.10(m, 2H), 6.86(d, 1H), 4.29-4.25(m, 4H), 2.34(s, 3H) 465.2/464.2
170 A ^Άι-Ν. ΗΝ-Ζ^Χ / 7V-(4- (dimethylamino)phenyl) -1 -(6-methylpyridin-2yl)-5-(quinoxalin-6-yl)lH-pyrazole-3carboxyamide 9.97(s, 1H), 8.95(s, 2H), 8.05-7.91(m, 3H), 7.76- 7.60(m, 4H), 7.33(br, 2H), 6.79-6.70(m, 3H), 2.86(s, 6H), 2.06(s, 3H) 450.2/449.2
171 A ν2Λμ~οο γγ^ ° 1 -(6-methylpyridin-2- yl)-N-(4- morpholinophenyl)-5- 8.87(s, 2H), 8.75(s, 1H), 8.09-8.04(m, 2H), 7.71- 7.63(m, 4H), 7.38(d, 1H), 492.2/491.2
106
(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 7.30(s, 1H), 7.18(d, 1H), 6.94(d, 2H), 3.88(t, 4H), 3.16(t, 4H), 2.35(s, 3H)
172 Ca 7J Ο 0 //-(4-(4- methylpiperazin-1 yl)phenyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide (300 MHz, DMSO-d6) δ 10.07(s, 1H), 8.97(s, 2H), 8.07-8.03(m, 2H), 7.96(t, 1H), 7.78-7.66(m, 4H), 7.36(s, 2H), 6.93(d, 2H), 3.31(s, 3H), 3.12-3.11(m, 4H), 2.25-2.22(m, 4H), 2.17(s, 3H) 505.2/504.2
173 CnXJ /V-(4-(4-acetylpiperazin- 1-yl)phenyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.91(s, 2H), 8.74(s, 1H), 8.08-8.03(m, 2H), 7.73- 7.63(m, 4H), 7.37(d, 1H), 7.29(s, 1H), 7.17(d, 1H), 6.96(d, 2H), 3.80-3.79(m, 2H), 3.65-3.63(m, 2H), 3.19- 3.14(m, 4H), 2.35(s, 3H), 2.15(s, 3H) 533.3/532.3
174 Δκ«-- /V-(4-cyanopheny 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 9.05(s, 1H), 8.88(s, 2H), 8.09-8.05(m, 2H), 7.88(d, 2H), 7.75-7.64(m, 4H), 7.35(d, 1H), 7.31(s, 1H), 7.21(d, 1H), 2.38(s, 3H) 432.2/431.1
107
175 f N CN /V-(3-cyanophenyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.97(s, 1H), 8.88(s, 2H), 8.15(s, 1H), 8.09-8.05(m, 2H), 7.96(d, 1H), 7.72- 7.65(m, 2H), 7.49-7.44(m, 2H), 7.36(d, 1H), 7.31(s, 1H), 7.20(d, 1H), 2.37(s, 3H) 432.2/431.1
176 NC ¢0^ /V-(2-cyanophenyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 9.56(s, 1H), 8.88(s, 2H), 8.66(d, 1H), 8.13(d, 1H), 8.05(d, 1H), 7.78(t, 1H), 7.71-7.64(m, 4H), 7.28(s, 1H), 7.21(t, 1H), 7.13(d, 1H), 2.19(s, 3H) 432.2/431.1
177 A <Ν±στ^ΝΛ 1 -(6-methylpyridin-2yl)-N-(4(morpholinomethyl)phen yl)-5-(quinoxalin-6-yl)lH-pyrazole-3carboxyamide 8.87(s, 3H), 8.09-8.04(m, 2H), 7.73-7.64(m, 4H), 7.38- 7.30(m, 4H), 7.18(d, 1H), 3.76-3.71(m,4H), 3.50(s, 2H), 2.48-2.45(m, 4H), 2.36(s, 3H) 506.2/505.2
178 A ^n-n HN-O-/ AH4-accty 1 phcny 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 9.04(s, 1H), 8.88(s, 2H), 8.1O-8.OO(m, 4H), 7.85(d, 2H), 7.75-7.65(m, 2H), 7.38(d, 1H), 7.32(s, 1H), 7.21(d, 1H), 2.61(s, 3H), 2.37(s, 3H) 449.2/448.2
108
179 /V-(3-acety 1phcny 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide (300 MHz, DMSO-d6) 10.5(s, 1H), 8.97(s, 2H), 8.46(br, 1H), 8.17(d, 1H), 8.07-8.04(m, 2H), 7.97(t, 1H), 7.79-7.76(m, 3H), 7.56(t, 1H), 7.37(s, 1H), 7.35(d,lH), 2.59(s, 3H), 2.18(s, 3H) 449.1/448.1
180 ί Ύί^ 0 1 -(6-methylpyridin-2- yl)-5-(quinoxalin-6-yl)- N-(4- (trifluoromethyl)phenyl) -1 //-pyrazolc-3carboxyamide (300 MHz, DMSO-d6) 10.6(s, 1H), 8.96(s, 2H), 8.11-7.93(m, 4H), 7.78- 7.72(m, 3H), 7.44(s, 1H), 7.35(d, 1H), 2.07(s, 3H) 475.1/474.1
181 ^>W CcA4” 1 -(6-methylpyridin-2- yl)-5-(quinoxalin-6-yl)- N-(3- (trifluoromethyl)phenyl) -1 //-pyrazolc-3carboxyamide (300 MHz, DMSO-d6) 10.6(s, 1H), 8.97(s, 2H), 8.33(br, 1H), 8.15(d, 1H), 8.O8-8.OO(m, 2H), 7.94(1, 1H), 7.79-7.74(m, 2H), 7.72(t, 1H), 7.43(d,lH), 7.38(s, 1H), 7.35(d, 1H), 2.08(s, 3H) 475.1/474.1
182 A 7V-(4- (methylcarbamoyl)phen (300 MHz, DMSO-d6) 464.1/463.1
109
yl)-1 -(6-methylpyridin- 2-yl)-5-(quinoxalin-6- yl)-1 H-pyrazole-3 carboxyamide 10.4(s, 1H), 8.94(s, 2H), 8.34(br, 1H), 8.06-7.91(m, 5H), 7.83-7.70(m, 4H), 7.40(s, 1H), 7.33(d, 1H), 2.77(s, 3H), 2.05(s, 3H)
183 ( /N iV-(4-fluorophenyl)-1 -(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.87-8.85(m, 3H), 8.08- 8.04(m, 2H), 7.73-7.64(m, 4H), 7.35(d, 1H), 7.30(s, 1H), 7.18(d, 1H), 7.07(t, 2H), 2.36(s, 3H) 425.1/424.1
184 < /N F ^N-N hn-TS ζΝ,λΑ/Μ r ° iV-(3-fluorophenyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 10.50(s, 1H), 8.97(s, 2H), 8.08-7.94(m, 3H), 7.84- 7.68(m, 4H), 7.42(s, 1H), 7.38-7.35(m, 2H), 6.95(t, 1H), 2.12(s, 3H) 425.2/421.1
185 ¢0^ iV-(2-fluorophenyl)-1 -(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 9.11(s, 1H), 8.87(s, 2H), 8.53(t, 1H), 8.11-8.04(m, 2H), 7.77-7.66(m, 2H), 7.51(d, 1H), 7.29(s, 1H), 7.20-7.ll(m, 4H), 2.28(s, 3H) 425.2/424.1
186 LL b ύ z z VJ' N-(3,4-difluorophenyl)- 1 -(6-methylpyridin-2- yl)-5-(quinoxalin-6-yl)- 8.87(s, 2H), 8.83(s, 1H), 8.08-8.04(m, 2H), 7.84- 7.80(m, 1H), 7.71-7.63(m, 2H), 7.35(d, 1H), 7.28(s, 2H), 443.1/442.1
110
lH-pyrazole-3- carboxyamide 7.25-7.17(m, 2H), 2.36(s, 3H)
8.98(s, 1H), 8.87(s, 2H),
N-(2,4-difluorophenyl)- 8.48-8.45(m, 1H), 8.10(d,
1 -(6-methylpyridin-2- 1H), 8.05(d, 1H), 7.74(t, 1H),
187 An F\ u x' rV!N-€>F yl)-5-(quinoxalin-6-yl)- 7.66(dd, 1H), 7.48(d, 1H), 443.1/442.1
lH-pyrazole-3- 7.28(s, 1H), 7.16(d, 1H),
carboxyamide 6.96-6.91(m, 2H), 2.28(s,
3H)
188 A-B N-(2,3-difluorophenyl)- 1 -(6-methylpyridin-2yl)-5-(quinoxalin-6-yl)lH-pyrazole-3carboxyamide 9.13(s, 1H), 8.88(s, 2H), 8.30(t, 1H), 8.11-8.04(m, 2H), 7.75(t, 1H), 7.67(dd, 1H), 7.50(d, 1H), 7.29(s, 1H), 7.19-7.12(m, 2H), 6.94(q, 1H), 2.28(s, 3H) 443.1/442.1
189 A N x VvrO-ci /V-(4-chlorophenyl)-1 - (6-methylpyridin-2-yl)- 5-(quinoxalin-6-yl)-1Hpyrazole-3carboxyamide 8.87(s, 3H), 8.08-8.04(m, 2H), 7.73-7.63(m, 4H), 7.36- 7.29(m, 4H), 7.18(d, 1H), 2.36(s, 3H) 441.1/440.1
190 A Cl ^^n-nhn-Ax /V-(2-chlorophenyl)-1 - (6-methylpyridin-2-yl)- 5-(quinoxalin-6-yl)-1H- 9.51(s, 1H), 8.87(s, 2H), 8.61(d, 1H), 8.12(d, 1H), 8.05(d, 1H), 7.77(t, 1H), 7.69(dd, 1H), 7.59(d, 1H), 441.1/440.1
Ill
pyrazole-3carboxyamide 7.43(dd, 1H), 7.34(t, 1H), 7.29(s, 1H), 7.15(d, 1H), 7.09(t, 1H), 2.23(s, 1H)
(300 MHz, DMSO-d6) δ
/V-(4-bromophenyl)-1 - 10.44 (s, 1H), 8.97(s, 2H),
(6-methylpyridin-2-yl)- 8.08-8.04(m, 2H), 7.96(t,
191 A N ' N H B r 5-(quinoxalin-6-yl)-1H- 1H), 7.84(d, 2H), 7.78- 485.1/484.1
rN ' 0
pyrazole-3- 7.71(m, 2H), 7.55(s, 2H),
carboxyamide 7.41(s, 1H), 7.36(d, 1H),
2.18(s, 3H)
(300 MHz, DMSO-d6) δ
iV-(6-methoxypyridin-3- 10.40 (s, 1H), 8.96(s, 2H),
yl)-1 -(6-methylpyridin- 8.59(d, 1H), 8.14-8.03(m,
192 -N A 2-yl)-5-(quinoxalin-6- 3H), 7.96(t, 1H), 7.77(d, 1H), 438.2/437.2
yl)-1 H-pyrazole-3 - 7.70(d, 1H), 7.40(s, 1H),
carboxyamide 7.36(d, 1H), 6.85(d, 1H),
3.85(s, 3H), 2.19(s, 3H)
AH4-mcthox ybcnzy 1)-1 - 8.86(s, 2H), 8.06-8.02(m,
/ /° (6-methylpyridin-2-yl)- 2H), 7.65(t, 2H), 7.33-
d 0
193 ^^n-n hn-/ 5-(quinoxalin-6-yl)-1H- 7.24(m, 5H), 7.12(d, 1H), 451.2/450.2
¢0^
pyrazole-3- 6.89(d, 2H), 4.61(d, 2H),
carboxyamide 3.81(s, 3H), 2.29(s, 3H)
112
194 , CN ct NHP ¢0^ /V-(4-cyanobenzy 1)-1 -(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.87(s, 2H), 8.06(d, 1H), 8.03(s, 1H), 7.69-7.62(m, 4H), 7.51-7.49(m, 3H), 7.30(d, 1H), 7.25(s, 1H), 7.16(d, 1H), 4.74(d, 2H), 2.33(s, 3H) 446.2/445.2
195 ¢0^° /V-(3-acetylbenzyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.07-8.02(m, 2H), 7.97(s, 1H), 7.88(d, 1H), 7.66-7.61(m, 3H), 7.49- 7.44(m, 2H), 7.32(d, 1H), 7.25(s, 1H), 7.14(d, 1H), 4.74(d, 2H), 2.62(s, 3H), 2.31(s, 3H) 463.2/462.2
196 6.. ,J /V-(4-fluorobenzy 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.06-8.02(m, 2H), 7.65-7.62(m, 2H), 7.38- 7.29(m, 4H), 7.25(s, 1H), 7.14(d, 1H), 7.04(t, 2H), 4.65(d, 2H), 2.31(s, 3H) 439.2/438.2
197 ¢0^° /V-(3-fluorobenzy 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.07-8.03(m, 2H), 7.66-7.63(m, 2H), 7.42(t, 1H), 7.34-7.30(m, 2H), 7.25(s, 1H), 7.18- 7.13(m, 3H), 6.98(t, 1H), 4.68(d, 2H), 2.31(s, 3H) 439.2/438.2
113
198 A. J >. iV-(2-fluorobenzyl)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.06-8.02(m, 2H), 7.67-7.62(m, 2H), 7.49- 7.33(m, 3H), 7.23(s, 1H), 7.15-7.04(m, 3H), 4.74(d, 2H), 2.30(s, 3H) 439.2/438.2
199 AH4-ch lorobcnzy 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.06-8.02(m, 2H), 7.68-7.62(m, 2H), 7.40(t, 1H), 7.32-7.30(m, 3H), 7.25(d, 2H), 7.14(d, 1H), 4.65(d, 2H), 2.31(s, 3H) 455.1/454.1
200 d Pci ^n-n HN-/ ¢0^° AH3-ch lorobcnzy 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.84(s, 2H), 8.05-8.01(m, 2H), 7.67-7.61(m, 2H), 7.36(s, 1H), 7.25-7.23(m, 5H), 7.13(d, 1H), 4.63(d, 2H), 2.78(s, 3H) 455.1/454.1
201 ¢0^ AH2-ch lorobcnzy 1)-1-(6methylpyridin-2-yl)-5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.86(s, 2H), 8.06-8.02(m, 2H), 7.67-7.62(m, 2H), 7.51- 7.49(m, 2H), 7.37-7.34(m, 2H), 7.26-7.23(m 2H), 7.14(d, 2H), 4.78(d, 2H), 2.80(s, 3H) 455.1/454.1
[00540] [Example 202] Preparation of A/-(2-fluorophenyl)-5-(qumoxalin-6-yl)-l(m-tolyl)-l//-pyrazole-3-carboxyamide
114 [00541]
Figure AU2017289021A1_D0045
[00542] A target compound (3 mg) was obtained in the same manner as in Example
160 except that phenylhydrazine was used instead of 2-hydrazinyl-6-methylpyridine hydrochloric acid in Step 3 of Preparation Example 3, and 2-fluoroaniline was used instead of p-anisidine of Example 160.
[00543] Ή NMR spectrum (300 MHz, CDC13) δ 9.08(s, 1H), 8.87(s, 2H), 8.53(t,
1H), 8.07-8.03(m, 2H), 7.59(dd, 1H), 7.32(s, 2H), 7.24-7.07(m, 6H), 2.37(s, 3H).
[00544] MS (ESI+): [M+H]+ m/z 424.2 [00545] [Examples 203 to 208] [00546] Compounds of Examples 203 to 208 listed in the following [Table 6] were obtained in the same manner as in Example 202.
[00547] [Table 61
Example Number Structure Compound Name ’H NMR Spectrum (300 MHz, CDChk) MS (ES) Actual Measurement Value [M+H]+ /Required Value
203 ΐ 0 l-(5-chloro-2- fluorophenyl)-/V-(4- 8.87-8.85(m, 2H), 8.67(s, 1H), 8.10(d, 1H), 7.97(d, 474.1/473.1
115
methoxyphenyl) -5- (quinoxalin-6-yl)-lHpyrazole-3carboxyamide 1H), 7.71-7.62(m, 4H), 7.40- 7.35(m, 1H), 7.33(s, 1H), 7.04(t, 1H), 6.92(d, 2H), 3.82(s, 3H)
l-(5-chloro-2- 8.86-8.85(m, 2H), 8.60(s,
fluoropheny 1)-^-(4- 1H), 8.10(d, 1H), 7.97(d,
Cl (dimethylamino)phenyl) 1H), 7.71-7.68(m, 2H),
204 e rtrCh 487.1/486.1
-5-(quinoxalin-6-yl)-1H- 7.57(d, 2H), 7.43-7.40(m,
pyrazole-3- 1H), 7.32(s, 1H), 7.03(t, 1H),
carboxyamide 6.75(d, 2H), 2.95(s, 3H)
iV-(4-methoxyphenyl)-5- 8.89-8.86(m, 2H), 8.73(s,
CF3 (quinoxalin-6-yl)-1 -(6- 1H), 8.14-8.02(m, 4H),
0 ΛΛ
205 b trifluoromethyl)pyridin- 7.73(d, 1H), 7.65(d, 2H), 491.1/490.1
2-yl)-1 H-pyrazole-3- 7.60(d, 1H), 6.93(d, 2H),
carboxyamide 3.82(s, 3H)
N-(4-
(dimethylamino)phenyl) 8.89-8.86(m, 2H), 8.65(s,
CF3 -5-(quinoxalin-6-yl)-1 -
ό 1H), 8.15-8.03(m, 4H),
206 e (6- 504.2/503.2
y o 7.74(d, 1H), 7.61-7.58(m,
N trifluoromethyl)pyridin- 3H), 6.77(d, 2H), 2.96(s, 6H)
2-yl)-1 H-pyrazole-3-
carboxyamide
116
207 Br A Γ I] 0 1 -(6-bromopyridin-2yl)-N-(4methoxyphenyl) -5(quinoxalin-6-yl)-lHpyrazole-3carboxyamide 8.89(s, 2H), 8.75(s, 1H), 8.13-8.10(m, 2H), 7.72- 7.63(m, 5H), 7.46-7.44(m, 1H), 6.93(d, 2H), 3.82(s, 3H) 501.1/500.1
208 Br A n 'ΑΤΟ' Γ I] 0 1 -(6-bromopyridin-2yl)-N-(4(dimethylamino)phenyl) -5-(quinoxalin-6-yl)-1Hpyrazole-3carboxyamide 8.88(s, 2H), 8.65(s, 1H), 8.12-8.09(m, 2H), 7.70(dd, 3H), 7.59(d, 2H), 7.44(d, 1H), 6.77(d, 2H), 2.95(s, 6H) 514.1/513.1
[00549] [Example 209] A-(2-Fluorophenvl)-l-(6-methvlpvridin-2-vl)-5(quinolin-4-vl)-lH-pyrazole-3-carboxvamide
Figure AU2017289021A1_D0046
Figure AU2017289021A1_D0047
[00551] After dissolving l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-177-pyrazole
3-carboxylic acid (40 mg, 0.1 mmol) synthesized in Step 5 of Preparation Example 4 in dichloromethane, HATU (55 mg, 0.1 mmol) and DIPEA (47 pL, 0.4 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature. To the reaction solution, 2-fluoro aniline (13 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was
117 added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (16 mg).
[00552] Ή NMR spectrum (300 MHz, CDC13) δ 9.17(s, 1H), 8.93(d, 1H), 8.55(t,
1H), 8.15(d, 1H), 7.69-7.60(m, 4H), 7.41(t, 1H), 7.33(d, 1H), 7.25-7.12(m, 4H), 6.95(d,
1H), 1.83(s, 3H).
[00553] MS (ESI+): [M+H]+ m/z 424.2 [00554] [Examples 210 to 217] [00555] Compounds of Examples 210 to 217 listed in the following [Table 7] were obtained in the same manner as in Example 209 using various amine derivatives instead of 2-fluoroaniline.
[00556] [Table 7]
Example Structure Compound Name Material Information
210 A o iV-(4-methoxyphenyl)-1 - (6-methylpyridin-2-yl)5-(quinolin-4-yl)-lHpyrazole-3carboxyamide Ή NMR (300 MHz, CDC13) δ 8.92(d, 1H), 8.78(s, 1H), 8.15(d, 1H), 7.72- 7.57(m, 5H), 7.48-7.40(m, 2H), 7.32(d, 1H), 7.26(s, 1H), 6.95(d, 3H), 3.83(s, 3H), 1.92(s, 3H). MS (ESI+): [M+H]+ m/z 436
211 \_/ \ 9 ^W-'O ο 1 -(6-methylpyridin-2yl)-N-(4(methylsulfonyl)phenyl) -5-(quinolin-4-yl)-1H- Ή NMR (300 MHz, CDC13) δ 9.13(s, 1H), 8.93(d, 1H), 8.16(d, 1H), 7.98(s, 4H), 7.71(t, 1H), 7.65-7.58(m, 2H), 7.44(d, 2H), 7.33-7.28(m, 2H), 6.98(d, 1H), 3.08(s, 3H), 1.96(s, 3H).
118
pyrazole-3carboxyamide MS (ESI+): [M+H]+ m/z 484
Ή NMR (300 MHz, CDC13) δ 8.92(d,
/V-(6-methoxypyridin-3- 1H), 8.81(s, 1H), 8.41(d, 1H), 8.17-
ό Ν /=Ν , yl)-1 -(6-methylpyridin- 8.13(m, 2H), 7.70-7.57(m, 3H), 7.45-
212 ν-ν ΗΝ- Ο νΛ° 2-yl)-5-(quinolin-4-yl)- 7.41(m, 2H), 7.31(d, 1H), 7.26(s, 1H),
lH-pyrazole-3- 6.96(d, 1H), 6.81(d, 1H), 3.96(s, 3H),
carboxyamide 1.95(s, 3H).
MS (ESI+): [M+H]+ m/z 437
/V-(6-chloropyridin-3- Ή NMR (300 MHz, CDC13) δ 8.99(s,
ό Ν Ζ=Ν yl)-1 -(6-methylpyridin- 1H), 8.92(d, 1H), 8.62(d, 1H), 8.40(d, 1H),
213 Ν-ν ΗΝ- Ο V^~CI 2-yl)-5-(quinolin-4-yl)- 8.15(d, 1H), 7.70-7.58(m, 3H), 7.45-
lH-pyrazole-3- 7.26(m, 5H), 6.97(d, 1H), 1.95(s, 3H).
carboxyamide MS (ESI+): [M+H]+ m/z 441
AMbcn zo| <71 [ 1,3 ] dioxol- Ή NMR (300 MHz, CDC13) δ 8.92(d,
5-yl)-l-(6- 1H), 8.8O(s, 1H), 8.15(d, 1H), 7.69-
/ Ν kA Μ ΗΝ- methylpyridin-2-yl)-5- 7.56(m, 3H), 7.49-7.42(m, 3H), 7.31(d,
214 Ν-Ν VAO
ίί kr Μ ό O-J (quinolin-4-yl)-1H- 1H), 7.24(s, 1H), 7.05(d, 1H), 6.94(d, 1H),
pyrazole-3- 6.81(d, 1H), 5.99(s, 2H), 1.95(s, 3H).
carboxyamide MS (ESI+): [M+H]+ m/z 450
iV-(3-fluoro-4- Ή NMR (300 MHz, CDC13) δ 8.90(d,
ΗΝ- ΓΆ αζ methoxyphenyl)-1 -(6-
215 I \\- ν#~° 1H), 8.85(s, 1H), 8.15(d, 1H), 7.70-
ίι η F methylpyridin-2-yl)-5-
(quinolin-4-yl)-1H- 7.59(m, 4H), 7.46-7.41(m, 3H), 7.32-
119
pyrazole-3carboxyamide 7.24(m, 2H), 6.97-6.93(m, 2H), 3.93(s, 3H), 1.95(s, 3H). MS (ESI+): [M+H]+ m/z 454
216 t N F\ N A-(2-fluoro-4methoxyphenyl)-1 -(6methylpyridin-2-yl)-5(quinolin-4-yl)-1Hpyrazole-3carboxyamide Ή NMR (300 MHz, CDC13) δ 8.948.92(m, 2H), 8.34(t, 1H), 8.15(d, 1H), 7.69-7.59(m, 4H), 7.41(t, 1H), 7.31(d, 1H), 7.23(s, 1H), 6.92(d, 1H), 6.76(d, 2H), 3.82(s, 3H), 1.83(s, 3H). MS (ESI+): [M+H]+ m/z 454
217 A 0 A- A-(4-(2methoxyethoxy)phenyl) - 1 -(6-methy lpyridin-2- yl)-5-(quinolin-4-yl)lH-pyrazole-3carboxyamide Ή NMR (300 MHz, CDC13) δ 8.92(d, 1H), 8.84(s, 1H), 8.15(d, 1H), 7.707.55(m, 5H), 7.48-7.41(m, 2H), 7.32-Ή NMR (300 MHz, CDC13) δ 7.24(m, 2H), 6.98-6.91(m, 3H), 4.15-4.10(m, 2H), 3.783.75(m, 2H), 3.46(s, 3H), 1.90(s, 3H). MS (ESI+): [M+H]+ m/z 480
[00558] [Example 218] 5-( Benzoic || 1,2,5 |oxadiazol-5-vl)-V-(4(cvclopropvlsulfonvl)phenvl)-l-(6-methvlpvridin-2-vl)-lH-pyrazole-3-carboxvamide [00559]
Figure AU2017289021A1_D0048
Figure AU2017289021A1_D0049
[00560] After dis so lving 5 - (benzo [c] [ 1,2,5 ] oxadiazo 1- 5 - yl) -1 - (6-methy lp yridin- 25 yl)-177-pyrazole-3-carboxylic acid (30 mg, 0.1 mmol) synthesized in Step 5 of Preparation
Example 5 in dichloromethane, HATU (43 mg, 0.1 mmol) and DIPEA (48 pL, 0.3 mmol)
120 were introduced thereto, and the result was stirred for 20 minutes at room temperature. To the reaction solution, 4-(cyclopropylsulfonyl)aniline (21 mg, 0.1 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (5 mg).
[00561] Ή NMR spectrum (300 MHz, CDC13) δ 9.02(s, 1H), 7.93(s, 4H), 7.847.75(m, 3H), 7.60(s, 1H), 7.31-7.26(m, 2H), 7.18(d, 1H), 2.50-2.45(m, 1H), 2.28(s, 3H), 1.39-1.34(m, 2H), 1.06-1.03(m, 2H).
[00562] MS (ESI+): [M+H]+ m/z 501 [00563] [Example 219] 5-(Ikmzo|d|oxazol-6-vl)-\-(2-fluorophenvl)-1-(6methvlpvridin-2-vl)-lH-pyrazole-3-carboxvamide [00564]
Figure AU2017289021A1_D0050
Figure AU2017289021A1_D0051
[00565] After dissolving 5-(benzo|<7|oxazol-6-yl)-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxylic acid (50 mg, 0.2 mmol) synthesized in Step 6 of Preparation Example 6 in dichloromethane, HATU (71 mg, 0.2 mmol) and DIPEA (81 pL, 0.5 mmol) were introduced thereto, and the result was stirred for 20 minutes at room temperature.
To the reaction solution, 2-fluoroaniline (17 mg, 0.2 mmol) was introduced, and the result was stirred for 12 hours at room temperature. After terminating the reaction, ethyl acetate was added thereto. The result was washed with sodium bicarbonate, then dried using
121 anhydrous magnesium sulfate, and after filtering, the filtrate was concentrated. The filtrate was purified using column chromatography to obtain a target compound (29 mg).
[00566] Ή NMR spectrum (300 MHz, CDC13) δ 9.09(s, 1H), 8.5l(t, 1H), 8.13(s,
1H), 7.74-7.70(m, 2H), 7.58(d, 1H), 7.34-7.26(m, 2H), 7.18-7.11(m, 5H), 2.37(s, 3H). [00567] MS (ESI+): [M+H]+ m/z 414 [00568] [Examples 220 to 227] [00569] Using compounds prepared in the preparation examples, compounds of
Examples 220 to 227 listed in the following [Table 8] were obtained in the same manner as in Example 219 using various amines instead of 2-fluoroaniline.
[00570] [Table 81
Example Structure Compound Name Material Information
Ή NMR (300 MHz, CDC13) δ
9.10(s, 1H), 8.14(s, 1H), 7.95-
/ 5-(benzo[d]oxazol-6-yl)-N-(4- 7.90(m, 4H), 7.75-7.65(m, 2H),
Q (cyclopropylsulfonyl)phenyl)-
220 HN-Qio 7.57(s, 1H), 7.29-7.15(m, 4H), 2.50-
1 -(6-methylpyridin-2-yl)-1H-
pyrazole-3-carboxyamide 2.45(m, 4H), 1.37-1.35(m, 2H),
1.05-1.02(m, 2H).
MS (ESI+): [M+H]+ m/z 500
Ή NMR (300 MHz, CDC13) δ
/ /V-cyclopropyl-5-(4-fluoro-3- 7.82 (s, 1H), 7.69-7.64 (m, 2H), 7.45
ά N (1 -(2-hydroxyethyl) AH-
Ji*/ Ό (d, 1H), 7.20-7.15 (m, 3H), 7.05-
221 pyrazol-4-yl)phenyl)-1-(6-
7.02 (m, 3H), 4.28 (t, 2H), 4.03 (t,
'_Ύη methylpyridin-2-yl)-lH- 2H), 2.70 (q, 1H), 2.47 (s, 3H), 0.88
pyrazole-3-carboxyamide (q, 2H), 0.69 (q, 2H).
122
MS (ESI+): [M+H]+m/z 447
Ή NMR (300 MHz, MeOD) δ
Ν-( 17f-pyrazol-4-yl)-5-(4- 8.52 (s, 2H), 8.20 (s, 1H), 8.00 (s,
Ο fluoro-3-(l-(2-hydroxyethyl)- 1H), 7.94 (t, 1H), 7.69 (d, 1H), 7.53
222 tl-CN ν-ήΗ 1 /7-py r azo 1 -4-y 1) phen y 1)-1-(6- (d, 1H), 7.40 (d, 1H), 7.21-7.18 (m,
^0Η methylpyridin-2-yl)-lH- 3H), 4.35 (t, 2H), 3.94 (t, 2H), 2.43
pyrazole-3-carboxyamide (s, 3H).
MS (ESI+): [M+H]+m/z 473
Ή NMR (300 MHz, MeOD) δ
N-( 1 -methyl- lH-pyrazol-4-yl)- 8.80 (s, 1H), 8.03 (s, 1H), 7.81 (s,
J 5-(4-fluoro-3-(l-(2-
άΝ 1H), 7.72-7.64 (m, 2H), 7.50-7.44
.ο hydroxyethyl)-1 H-pyrazol-4-
223 Χ> Η Μ, (m, 2H), 7.19-7.03 (m, 5H), 4.26 (t,
yl)phenyl)-1 -(6-methylpyridin- 2H), 4.04 (t, 2H), 3.89 (s, 3H), 2.48
2-yl)-1 H-pyrazole-3- (s, 3H).
carboxyamide MS (ESI+): [M+H]+m/z 487
Ή NMR (300 MHz, CDC13) δ
N-(l -(methylsulfonyl)- 1H- 9.04 (s, 1H), 8.60 (s, 1H), 7.99 (s,
pyrazol-4-yl)-5-(4-fluoro-3-(l-
ό 1H), 7.83 (s, 1H), 7.71-7.66 (m, 2H),
^Ν·Ν ο (2-hydroxyethyl)-1/7-pyrazol-
224 X·77 ο σ' 7.46 (d, 1H), 7.24-7.05 (m, 5H), 4.30
4-yl)phenyl)-1-(6-
'Nju (t, 2H), 4.05 (t, 2H), 3.33 (s, 3H),
methylpyridin-2-yl)-lH- 2.51 (s, 3H).
pyrazole-3-carboxyamide MS (ESI+): [M+H]+m/z 551
123
Ή NMR (300 MHz, CDC13) δ
iV-(4-chlorophenyl)-5-(4- 8.89 (s, 1H), 7.84 (s, 1H), 7.74-7.69
o fluoro-3-(l-(2-hydroxyethyl)- (m, 3H), 7.52 (d, 1H), 7.35 (d, 2H),
225 ^O“ci l/7-pyrazol-4-yl)phenyl)-1-(6- 7.25-7.16 (m, 2H), 7.09 (d, 2H), 4.31
methylpyridin-2-yl)-lH- (t, 2H), 4.06 (t, 2H), 3.33 (s, 3H),
pyrazole-3-carboxyamide 2.52 (s, 3H).
MS (ESI+): [M+H]+m/z 517
Ή NMR (300 MHz, CDC13) δ
iV-(4-(methylsulfonyl)phenyl)- 9.13 (s, 1H), 7.96 (s, 3H), 7.84 (s,
/ 5-(4-fluoro-3-(l-(2-
1H), 7.75-7.70 (m, 2H), 7.50 (d,
hydroxyethyl)- l/Tpyrazol-4-
226 1H), 7.24-6.77 (m, 6H), 4.31 (t, 2H),
'^H yl)phenyl)-1 -(6-methylpyridin- 4.06 (t, 2H), 3.08 (s, 3H), 2.53 (s,
2-yl)-1 H-pyrazole-3- 3H).
carboxyamide MS (ESI+): [M+H]+m/z 561
Ή NMR (300 MHz, CDC13) δ
J iV-(2-fluoropheny 1)-5- 9.98(s, lH),9.11(s, 1H), 8.41(s, 1H),
M (thieno[3,2,c]pyridin-2-yl)-1 - 7.95(d, 2H), 7.80(s, 1H), 7.80(s,
227 ς n-n ΑΧ i '5- 0
Il (m-tolyl)- l/Tpyrazole-3 - 2H), 7.70(d, 1H), 7.50(d, 1H), 7.28-
carboxyamide 7.23(m, 4H), 2.42(s, 3H)
MS (ESI+): [M+H]+m/z 429
[00572] Formulation Example 1: Preparation of Tablet [00573] In accordance with common methods, a single tablet for oral administration containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 9 in amounts corresponding thereto.
[00574] [Table 91
124
Ingredient Amount per Tablet
Active Compound 100 mg
Corn Starch 80 mg
Lactose 80 mg
Magnesium Stearate 5 mg
[00575] Formulation Example 2: Preparation of Capsule [00576] In accordance with common methods, a hard gelatin capsule for oral administration containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 10 in amounts corresponding thereto.
[00577] [Table 101
Ingredient Amount per Capsule
Active Compound 100 mg
Corn Starch 80 mg
Lactose 80 mg
Crystalline Cellulose 80 mg
Magnesium Stearate 5 mg
[00578] Formulation Example 3: Preparation of Formulation for Injection [00579] In accordance with common methods, a formulation for injection containing each of the compounds prepared in Examples 1 to 227 as an active compound was prepared using ingredients of the following Table 11 in amounts corresponding thereto. However, a pH was not adjusted when using a salt of the compound of Chemical Formula 1 as the active compound.
125 [00580] [Table 11]
Ingredient Amount per Formulation for Injection
Active Compound 20 mg
5% Glucose Solution 10 mL
HC1(1 N) Suitable Amount to Make pH to 4
[00581] Formulation Example 4: Preparation of Formulation for Injection [00582] In accordance with common methods, a formulation for injection containing each of the compounds prepared in Examples 1 to 227 as an active compound 5 was prepared using ingredients of the following Table 12 in amounts corresponding thereto.
[00583] [Table 12]
Ingredient Amount per Formulation for Injection
Active Compound 20 mg
Polyethylene Glycol 400 2 mL
Sterilized Water 8 mL
[00584] Experimental Example 1: Activity Inhibition Test on ALK5 Enzyme [00585] For each of the compounds obtained in Examples 1 to 227, inhibitory activity against ALK5 kinase was measured.
[00586] For this, a LanthaScreen Eu binding kinase assay method was used, and
ALK5 kinase, a kinase buffer, a kinase tracer 178, and a LanthaScreen Eu-GST binding antibody were all purchased from Thermo Fisher Scientific Solutions. Each of the compounds was made into a 10 mM DMSO solution, and diluted by 1/10 to a concentration 15 of 1 μΜ to 0.0001 μΜ with an aqueous solution containing 4% DMSO. The test was performed in 384 well plates (well polystyrene low volume round-bottomed plates).
126
First, 5 pL of the diluted compound solution was added, then 5 pL of the kinase/antibody mixture solution was introduced thereto, and 5 pL of the tracer was introduced thereto. Herein, these were added to each well so that the final kinase concentration became 5 nM, the final Eu-GST binding antibody concentration 2 nM, and the kinase tracer 178 5 concentration 10 nM, and the result was reacted in a stirrer for 60 minutes at room temperature. Then a fluorescence value was measured using a fluorescence meter (molecular device) (620 nm excitation filter, 665 nm emission filter). Herein, as for the degree of compound activity to inhibit the kinase reaction, a phosphorylate rate was calculated from 0% to 100% with respect to a control group according to the protocol 10 included in the kit, and a 50% inhibitory concentration (IC50) value was calculated by obtaining the x-axis concentration in the region where 50% activity was inhibited. The IC50 results for each of the compounds are shown in the following Table 13.
[00587] [Table 131
IC50(nM)
Example ALK5 Example ALK5 Example ALK5
1 5.0 41 5.2 81 1.5
2 4.7 42 2.2 82 2.7
3 12 43 4.4 83 0.7
4 4.4 44 13 84 3.9
5 10-100 45 2.4 85 3.8
6 11 46 1.3 86 1.1
7 < 10 47 1.2 87 9.1
8 4.7 48 4.1 88 3.5
9 19 49 5.6 89 3.5
127
10 10
11 2.2
12 6.1
13 10-100
14 17
15 6.4
16 2.3
17 14
18 10-100
19 10-100
20 10-100
21 -100
22 10-100
23 -10
24 -100
25 < 10
26 10-100
27 6.2
28 4.5
29 3.9
30 5.8
31 > 100
32 10-100
33 10-100
50 6.6
51 6.5
52 2.5
53 2.4
54 2.0
55 4.2
56 2.4
57 45
58 5.6
59 20
60 13
61 10-100
62 16
63 3.7
64 < 10
65 < 10
66 3.2
67 9.6
68 65
69 4.9
70 4.6
71 8.0
72 11
73 5.8
90 5.0
91 10-100
92 10-100
93 3.9
94 -10
95 25
96 3.5
97 10-100
98 5.3
99 -10
100 10-100
101 10-100
102 10-100
103 9.1
104 7.0
105 7.0
106 14
107 10-100
108 -10
109 9.7
110 10-100
111 > 100
112 10-100
113 10-100
128
34 10-100
35 10-100
36 < 10
37 40
38 1.8
39 2.4
40 3.3
74 2.3
75 7.4
76 -10
77 7.2
78 3.4
79 5.6
80 1.3
114 9.5
115 10-100
116 -10
117 10-100
118 10-100
119 < 10
120 10-100
IC50(nM)
Example ALK5 Example ALK5 Example ALK5
121 10-100 157 10-100 193 -100
122 10-100 158 10-100 194 >100
123 10-100 159 10-100 195 10-100
124 31 160 10-100 196 100
125 10-100 161 10-100 197 10-100
126 -10 162 2.0 198 <100
127 -100 163 4.6 199 >100
128 10-100 164 18 200 10-100
129 10-100 165 24 201 10-100
130 10-100 166 -100 202 >1,000
131 10-100 167 <100 203 >100
132 -10 168 <100 204 -100
133 10-100 169 10-100 205 >100
134 10-100 170 <100 206 >100
129
135 10-100 171 10-100 207 10-100
136 -10 172 10-100 208 10-100
137 10-100 173 10-100 209 > 100
138 10-100 174 <100 210 10-100
139 10-100 175 <100 211 < 10
140 -10 176 100 212 36
141 10-100 177 -100 213 23
142 10-100 178 10-100 214 30
143 6.6 179 <100 215 91
144 10-100 180 100-1,000 216 -100
145 15 181 -100 217 18
146 6.0 182 <100 218 10-100
147 3.7 183 10-100 219 27
148 8.3 184 10-100 220 3.2
149 7.7 185 <100 221 4.3
150 4.8 186 10-100 222 1.0
151 2.7 187 10-100 223 2.8
152 4.6 188 100 224 3.1
153 25 189 10-100 225 33
154 -10 190 100-1,000 226 4.7
155 13 191 10-100 227 -100
156 22 192 10-100
[00589] Hereinbefore, the present disclosure has been described with reference to the examples, however, these are for illustrative purposes only, and it is to be understood
130 that various modified and equivalent other examples of the present disclosure obvious to those skilled in the art may be implemented within the scope of the attached claims.
131
A compound of the following Chemical Formula 1 or a pharmaceutically

Claims (155)

[Claim 1] acceptable salt thereof: [Chemical Formula 1] wherein, in Chemical Formula 1, (Rj)m X is N or CH; a ring A is C3-6 cycloalkylene, Ce-io arylene, C5-10 heteroarylene containing 1 to 4
1 H-p yr azo le-3-carboxy amide;
(217) 2V-(4-(2-methoxyethoxy)phenyl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4yl)- l//-pyrazole-3-carboxyamide;
(218) 5-(benzo[c] [1,2,5]oxadiazol-5-yl)-2V-(4-(cyclopropylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 //-p yrazo le- 3 -carboxy amide;
(219) 5-(benzo[d]oxazol-6-yl)-2V-(2-fluorophenyl)-l-(6-methylpyridin-2-yl)-l//pyrazole-3-carboxyamide;
152
(220) 5-(benzo[d]oxazol-6-yl)-A-(4-(cyclopropylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(221) A-cyclopropyl-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol-4yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(222) A-(177-pyrazol-4-yl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol-4yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(223) A-(l-methyl-177-pyrazol-4-yl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177pyrazol-4-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(224) N-( l-(methylsulfonyl)-177-pyrazo 1-4-yl)-5-(4-fluoro-3-( 1-(2hydroxyethyl)- 177-pyrazol-4-yl)phenyl)- l-(6-methylpyridin-2-yl)-1 //-pyrazole-3carboxyamide;
(225) A-(4-chlorophenyl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177-pyrazol-4yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(226) A-(4-(methylsulfonyl)phenyl)-5-(4-fluoro-3-(l-(2-hydroxyethyl)-177pyrazol-4-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide; and (227) A-(2-fluorophenyl)-5-(thieno[3,2,c]pyridin-2-yl)-l-(m-tolyl)-177-pyrazole3-carboxyamide.
[Claim 51
A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of Claim 1 in a pharmaceutically effective amount.
[Claim 61
A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of Claim 4 in a pharmaceutically effective amount.
[Claim 7]
153
A method for inhibiting a TGF-β signaling pathway in a subject or a cell, the method comprising administering a pharmaceutically effective amount of the compound of Claim 1 to the subject in need.
[Claim 81
A method for inhibiting a TGF-β signaling pathway in a subject or a cell, the method comprising administering a pharmaceutically effective amount of the compound of Claim 4 to the subject in need.
[Claim 91
A method for treating or preventing a fibrotic disease or a fibrotic condition in a subject, the method comprising administering a pharmaceutically effective amount of the compound of Claim 1 to the subject in need.
[Claim 101
The method of Claim 9, wherein the fibrotic disease or fibrotic condition is selected from the group consisting of scleroderma, idiopathic pulmonary fibrosis, glomerulonephritis, diabetic nephrosis, lupus nephrosis, hypertension-induced nephrosis, eye scar, corneal scar, liver fibrosis, biliary duct fibrosis, pulmonary fibrosis, acute lung injury, postinfarction cardiac fibrosis, fibrosclerosis, fibrous cancer, fibroid, fibroma, fibroadenoma or fibrosarcoma.
[Claim 11]
A method for inhibiting metastasis of cancer cells in a subject, the method comprising administering a pharmaceutically effective amount of the compound of Claim 1 to the subject in need.
[Claim 12]
A method for treating a carcinoma mediated by overexpression of ΤΟΡβ, the method comprising administering a pharmaceutically effective amount of the compound
1 H-p yr azo le-3-carboxy amide;
(216) 2V-(2-fluoro-4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-
1 H-p yr azo le-3-carboxy amide;
(215) 2V-(3-fluoro-4-methoxyphenyl)-l-(6-niethylpyridin-2-yl)-5-(quinolin-4-yl)-
1 //-p yr azo le-3-carboxy amide;
(212) A^-(6-methoxypyridin-3-yl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-l//pyrazole-3-carboxyamide;
(213) 2V-(6-chloropyridin-3-yl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-l//pyrazole-3-carboxyamide;
(214) 2V-(benzo[d] [l,3]dioxo 1-5-yl)-l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-
1 H-p yr azo le-3-carboxy amide;
1 H-p yr azo le-3-carboxy amide;
1 H-p yrazo le-3-carboxy amide;
1 H-p yrazo le-3-carboxy amide;
1 //-p yr azo le-3-carboxy amide;
1 H-p yr azo le-3-carboxy amide;
(1) 5-(benzo[<i]thiazol-6-yl)-A-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-l//pyrazole-3-carboxyamide;
1, m and n are each independently an integer of 0 to 4.
[Claim 2]
The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein X is N, and Ri is C1-6 alkyl.
[Claim 31
The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein the ring A is phenyl, pyrazole, pyridinyl or benzo[d][l,3]dioxol.
[Claim 4]
The compound or a pharmaceutically acceptable salt thereof of Claim 1, wherein the compound of Chemical Formula 1 is a compound selected from the group consisting of the following compounds:
2-yl)-177-pyrazole-3-carboxyamide;
(2) 5-(benzo[<i]thiazol-6-yl)-A-(4-ethoxyphenyl)- l-(6-methylpyridin-2-yl)- \Hpyrazole-3-carboxyamide;
(3) 5-(benzo[<i]thiazol-6-yl)-A-(4-(cyclopropylmethoxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(4) 5-(benzo[<i]thiazol-6-yl)-A-(4-(2-methoxyethoxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
134
5-(benzo[<7]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4-(5- methylsulfonimidoyl)phenyl)-177-pyrazole-3-carboxyamide;
5- (benzo | <71 thiazo 1- 6- yl) -1 - (6-methy lp yridin- 2- yl) -N- (4- (methylsulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
(5) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-A^-(4(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
6-yl)- l/7-pyrazole-3-carboxyamide;
(178) 2V-(4-acetylphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(179) 2V-(3-acetylphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(180) l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-2V-(4(trifluoromethyl)phenyl)-177-pyrazole-3-carboxyamide;
(181) l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-2V-(3- (trifluoromethyl)phenyl)-177-pyrazole-3-carboxyamide;
(182) 2V-(4-(methylcarbamoyl)phenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
(183) 2V-(4-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
149
(184) 2V-(3-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(185) 2V-(2-fluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(186) 2V-(3,4-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(187) 2V-(2,4-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(188) 2V-(2,3-difluorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(189) 2V-(4-chlorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(190) 2V-(2-chlorophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(191) 2V-(4-bromophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(192) 2V-(6-methoxypyridin-3-yl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)177-p yr azo le-3-carboxy amide;
(193) 2V-(4-methoxybenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(194) 2V-(4-cyanobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(195) 2V-(3-acetylbenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
150
(196) 7V-(4-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(197) 7V-(3-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(198) 7V-(2-fluorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(199) 7V-(4-chlorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(200) 7V-(3-chlorobenzyl)- l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(201) 7V-(2-chlorobenzyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(202) 7V-(2-fluorophenyl)-5-(quinoxalin-6-yl)-l-(m-tolyl)-177-pyrazole-3carboxyamide;
(203) l-(5-chloro-2-fluorophenyl)-7V-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(204) l-(5-chloro-2-fluorophenyl)-7V-(4-(dimethylaniino)phenyl)-5-(quinoxalin6-yl)-177-pyrazole-3-carboxyamide;
(205) 7V-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-l-(6-trifluoroniethyl)pyridin-2yl)-177-pyrazole-3-carboxyamide;
(206) Af-(4-(dimethylamino)phenyl)-5-(quinoxalin-6-yl)-1-(6trifluoromethyl)p yridin- 2- y 1) -177-p yr azo le- 3 -carboxy amide;
(207) l-(6-bromopyridin-2-yl)-7V-(4-methoxyphenyl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
151
(208) l-(6-bromopyridin-2-yl)-Af-(4-(dimethylamino)phenyl)-5-(quinoxalin-6- yl)-I //-pyrazolc-3-carboxyamidc;
(209) 2V-(2-fluorophenyl)- l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-1//pyrazole-3-carboxyamide;
(210) 2V-(4-methoxyphenyl)- l-(6-methylpyridin-2-yl)-5-(quinolin-4-yl)-1//pyrazole-3-carboxyamide;
(211) l-(6-methylpyridin-2-yl)-2V-(4-(methylsulfonyl)phenyl)-5-(quinolin-4-yl)-
(6) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(benzyloxy)phenyl)-l-(6-methylpyridin-2-yl)-
6-membered ring with the ring A, one or more heteroatoms selected from among N, O and S atoms are included in the ring, and the heteroatoms are further oxidized;
R4 and R5 are each independently hydrogen, linear or branched C1-6 alkyl, linear
(7) 2V-(benzo[<7][l,3]dioxol-5-yl)-5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2yl)- l-77-pyrazole-3-carboxyamide;
(8) 5-(benzo[<7]thiazol-6-yl)-2V-(4-fluoro-3-methoxyphenyl)-l-(6-niethylpyridin2-yl)-177-pyrazole-3-carboxyamide;
(9) 5-(benzo[<7]thiazol-6-yl)-2V-(2-fluoro-4-methoxyphenyl)-l-(6-niethylpyridin-
(10) 5-(benzo[<7]thiazol-6-yl)-A^-(3-fluoro-4-methoxyphenyl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxyamide;
10 heteroatoms selected from among N, O and S atoms, or a non-aromatic fused heteropolycyclic ring containing 1 to 4 heteroatoms selected from among N, O and S;
Ris are each independently hydrogen, halogen, or linear or branched C1-6 alkyl, or halo C1-6 alkyl, and when there are a plurality of Ris, these are the same as or different from each other;
132
R3 is hydrogen, halogen, linear or branched Ci-6 alkyl, linear or branched halo Ci5 6 alkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl unsubstituted or substituted with R4, Ce-io heterobicycloalkyl, linear or branched C2-6 alkenyl, C2-6 alkynyl, -(CH2)a-R4, -(CH2)a-OR4, -(CH2)a-O-(CH2)a-R4, -(CH2)a-S-(CH2)a-R4, -(CH2)a-O-(CH2)a-OR4, -(CH2)a-NR4R5, (CH2)a-NO2, -(CH2)a-CN, -(CH2)a-COR4, -(CH2VCO2R4, -(CH2)a-CONR4R5, -(CH2)aNHCOR4, -(CH2)a-SR4, -(CH2)a-NHSO2R4, -(CH2)aSOR6, -(CH2)a-SO2R6, -(CH2)a10 SO2NHR6, -(CH2)a-SO(NH)R6 or -(CH2)a-SO2NR4Rs, or when there are a plurality of R3S and they are adjacent to each other, they are linked to each other to form a 5-membered or
(11) 5-(benzo[<7]thiazol-6-yl)-2V-(3-aminophenyl)-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(12) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(methylamino)phenyl)-l-(6-methylpyridin-2yl)-177-pyrazole-3-carboxyamide;
(13) 5-(benzo | <71thiazo 1-6- yl)-N-(4-(dimethylamino)pheny 1)-1 -(6-methyipyridin2-yl)-177-pyrazole-3-carboxyamide;
(14) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-nitrophenyl)-177pyrazole-3-carboxyamide;
(15) 5-(benzo[<7]thiazol-6-yl)-A^-(4-((2-(dimethylamino)ethyl)(methyl)amino) phenyl)- l-(6-methylpyridin-2-yl)- 177-pyrazole-3-carboxyamide;
15 or branched halo C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkenyl, C1-6 carbonyl, C6-12 aryl, (CH2)b-NR6R7, or saturated or partially unsaturated 5-membered to 10-membered
(16) 5 - (benzo [d] thiazo 1- 6- yl) -N- (4-(3- (dimethylamino )p yrro lidin- l-yl)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
135
(17) 5-(benzo[<7]thiazol-6-yl)-A^-(3-chloro-4-(octahydro-677-pyrrolo[3,4£]pyridin-6-yl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyaniide;
(18) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-phenyl-177-pyrazole-3carboxyamide;
(19) 5-(benzo[<7]thiazol-6-yl)-7V-(3-tolyl)-l-(6-methylpyridin-2-yl)-177-pyrazole3-carboxyamide;
(20) 5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(3-vinylphenyl)-177pyrazole-3-carboxyamide;
(21) 5-(benzo[<7]thiazol-6-yl)-7V-(3-(trifluoromethyl)phenyl)-l-(6-methylpyridm2-yl)-177-pyrazole-3-carboxyamide;
(22) 5-(benzo[<7]thiazol-6-yl)-7V-(3-(cyanophenyl)-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(23) 5-(benzo[<7|thiazol-6-yl)-7V-(3-acetylphenyl)- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(24) ethyl 3-(5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)- 177-pyrazole-3carboxy amido )benzo ate;
(25) 5-(benzo[<7|thiazol-6-yl)-7V-(4-(methylcarbamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3-carboxyamide;
(26) 5-(benzo[<7]thiazol-6-yl)-7V-(4-acetamidophenyl)-l-(6-methylpyridin-2-yl)177-p yrazo le-3-carboxy amide;
(27) 5-(benzo[<7|thiazol-6-yl)-7V-(2-fluorophenyl)- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(28) 5-(benzo[<7|thiazol-6-yl)-7V-(3-fluorophenyl)- l-(6-methylpyridin-2-yl)-177- pyrazole-3-carboxyamide;
136
(29) 5-(benzo[</]thiazol-6-yl)-A^-(4-fluorophenyl)- l-(6-methylpyridin-2-yl)-1//pyrazole-3-carboxyamide;
(30) 5-(benzo[<i]thiazol-6-yl)-iV-(3,4-difluorophenyl)-l-(6-methylpyridin-2-yl)-
(31) 5-(benzo[<Z]thiazol-6-yl)-2V-(2-chlorophenyl)- l-(6-methylpyridin-2-yl)-1//pyrazole-3-carboxyamide;
(32) 5-(benzo[<Z]thiazol-6-yl)-2V-(3-chlorophenyl)- l-(6-methylpyridin-2-yl)-1//pyrazole-3-carboxyamide;
(33) 5-(benzo[<Z]thiazol-6-yl)-2V-(4-chlorophenyl)- l-(6-methylpyridin-2-yl)-1//pyrazole-3-carboxyamide;
(34) 5-(benzo[<Z]thiazol-6-yl)-2V-(4-bromophenyl)- l-(6-methylpyridin-2-yl)-1//pyrazole-3-carboxyamide;
(35) 5-(benzo[<Z]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-iV-(3(methylthio )phenyl) -1 Z/-p yrazo le-3-carboxy amide;
(36) 5-(benzo[<Z]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4(methylthio )phenyl) -1 Z/-p yrazo le-3-carboxy amide;
(37) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(cyclopropylthio)phenyl)-l-(6-methylpyridin2-yl)-l//-pyrazole-3-carboxyamide;
(38) 5-(benzo[</]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3(methylsulfinyl)phenyl)-l//-pyrazole-3-carboxyamide;
(39) 5-(benzo[</]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-2V-(4- (methylsulfinyl)phenyl)-l//-pyrazole-3-carboxyamide;
(40) 5-(benzo[</]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-2V-(3(methylsulfonyl)phenyl)-l//-pyrazole-3-carboxyamide;
137
(41)
(42) 5-(benzo [<i] thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(4(propylsulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
(43) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(cyclopropylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(44) 5-(benzo[<7]thiazol-6-yl)-2V-(2-fluoro-4-(methylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(45) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3-sulfamoylphenyl)-
(46) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-sulfamoylphenyl)-
(47) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(3-(iVmethylsulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
(48) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-2V-(4-(iVmethylsulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
(49) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(2V-cyclopropylsulfamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(50) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(2V-cyclopropylsulfamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(51) 5-(benzo[<7]thiazol-6-yl)-2V-(3-(2V,2V-dimethylsulfamoyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(52) 5-(benzo[<7]thiazol-6-yl)-2V-(4-(2V,2V-dimethylsulfamoyl)phenyl)-1-(6- methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
138
(53) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-A^-(3(methylsulfonamido)phenyl)-177-pyrazole-3-carboxyamide;
(54) 5-(benzo[<7]thiazol-6-yl)-7V-(3-(cyclopropanesulfonamido)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(55) 5-(benzo[<7]thiazol-6-yl)-7V-(4-(cyclopropanesulfonamido)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(56) 4-(5-(benzo[<7]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)- l/¥-pyrazole-3carboxyamido)benzenesulfonic acid;
(57) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4((trifluoromethyl)sulfonyl)phenyl)-177-pyrazole-3-carboxyamide;
(58) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4-(7V-(2,2,2trifluoroethyl)sulfamoyl)phenyl)-177-pyrazole-3-carboxyamide;
(59) 5-(benzo[<7]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4((methylsulfonyl)methyl)phenyl)-177-pyrazole-3-carboxyamide;
(60) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(3(sulfamoylmethyl)phenyl)-177-pyrazole-3-carboxyamide;
(61) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(4(sulfamoylmethyl)phenyl)-177-pyrazole-3-carboxyamide;
(62) 5-(benzo[<7]thiazol-6-yl)-7V-(4-fluoro-3-(sulfamoylmethyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(63) 5-(benzo[<7]thiazol-6-yl)-7V-(4-((l,l-dioxidotetrahydrothiophen-3yl)amino)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(64) 5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(pyridin-4-yl)-177pyrazole-3-carboxyamide;
139
(65) 5-(benzo[<7]thiazol-6-yl)-A^-(6-methoxypyridin-3-yl)-l-(6-methylpyridin-2- yl)- 177-pyrazole-3-carboxyamide;
(66) 5-(benzo[<7]thiazol-6-yl)-A^-(2-methoxypyridin-4-yl)-l-(6-methylpyridin-2- yl)- 177-pyrazole-3-carboxyamide;
(67) 5-(benzo[<7]thiazol-6-yl)-A^-(6-(methylthio)pyridin-3-yl)-l-(6-methylpyridin2-yl)-177-pyrazole-3-carboxyamide;
(68) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(6(methylsulfonyl)pyridin-2-yl)-177-pyrazole-3-carboxyamide;
(69) 5-(benzo[<7]thiazol-6-yl)-7V-(6-(methylsulfonyl)pyridin-3-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(70) 5-(benzo[<7]thiazol-6-yl)-l-(6-methylpyridin-2-yl)-7V-(2(methylsulfonyl)pyridin-4-yl)-177-pyrazole-3-carboxyamide;
(71) 5-(benzo[<7]thiazol-6-yl)-2V-(6-fluoropyridin-3-yl)-l-(6-methylpyridin-2-yl)177-p yrazo le-3-carboxy amide;
(72) 5-(benzo[<7]thiazol-6-yl)-A^-(2-fluoropyridin-4-yl)-l-(6-methylpyridin-2-yl)-
177-p yrazo le-3-carboxy amide;
(73) 5-(benzo[<7]thiazol-6-yl)-2V-(6-chloropyridin-3-yl)-l-(6-methylpyridin-2-yl)-
177-p yrazo le-3-carboxy amide;
(74) 5-(benzo[<7]thiazol-6-yl)-2V-(2-chloropyridin-4-yl)-l-(6-methylpyridin-2-yl)177-p yrazo le-3-carboxy amide;
(75) 5-(benzo[<7]thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-7V-(thiazo 1-2-yl)-177pyrazole-3-carboxyamide;
(76) 5-(benzo[<7]thiazol-6-yl)-7V-benzyl-l-(6-methylpyridin-2-yl)-177-pyrazole-3carboxyamide;
140
(77) 5-(benzo[<7]thiazol-6-yl)-A^-(2-fluorobenzyl)- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(78) 5-(benzo[<7|thiazol-6-yl)-7V-(3-fluorobenzyl)-l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(79) 5-(benzo[<7]thiazol-6-yl)-A^-(4-fluorobenzyl)- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(80) 5-(benzo[d]thiazo 1-6-yl)-l-(6-methylpyridin-2-yl)-7V-(l-(methylsulfonyl)177-p yrazo 1-4- yl) -177-p yrazo le- 3 -carboxy amide;
(81) 5-(benzo[d]thiazol-6-yl)-7V-(l-(cyclopropylsulfonyl)-177-pyrazo 1-4-yl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(82) 5-(benzo[<7]thiazol-6-yl)-7V-(3-hydroxyphenyl)-l-(6-methylpyridin-2-yl)177-p yrazo le-3-carboxy amide;
(83) 5-(benzo[<7]thiazol-6-yl)-7V-(4-hydroxyphenyl)-l-(6-methylpyridin-2-yl)177-p yrazo le-3-carboxy amide;
(84) 5-(benzo[<7]thiazol-6-yl)-7V-(3-(hydroxymethyl)phenyl)-l-(6-niethylpyridin2-yl)-177-pyrazole-3-carboxyamide;
(85) 5-(benzo[<7]thiazol-6-yl)-7V-(4-(hydroxymethyl)phenyl)-l-(6-niethylpyridin2-yl)-177-pyrazole-3-carboxyamide;
(86) 7V-(4-aminophenyl)-5-(benzo[<7|thiazo 1-6-yl)- l-(6-methylpyridin-2-yl)-177pyrazole-3-carboxyamide;
(87) 5-(benzo[<7|thiazol-6-yl)-7V-(4-(butylamino)phenyl)-l-(6-methylpyridin-2yl)- 177-pyrazole-3-carboxyamide;
(88) 5-(benzo[<7]thiazol-6-yl)-7V-(4-(cyclopropylamino)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
141
(89)
(90) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(91) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(92) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(93) 5-([l,2,4] triazolo [l,5-a]pyridin-6-yl)-2V-(4-hydroxyphenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(94) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-isopropylphenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(95) 5-([ 1,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(2-methoxyethoxy)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(96) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(benzo[d][l,3]dioxo 1-5-yl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(97) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(2-fluoro-4-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(98) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-fluoro-4-methoxyphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(99) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(2(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
(100) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(3- (trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
142
(101) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(4(trifluoromethoxy)phenyl)-177-pyrazole-3-carboxyamide;
(102) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(3-(dimethylamino)phenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(103) 5-([ 1,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-aminophenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(104) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(dimethylamino)phenyl)-1-(6methy lp yridin- 2- yl) -1 -H-p yrazo le- 3 -carboxy amide;
(105) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(pyrro lidin- l-yl)phenyl) 1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(106) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-((2(dimethylamino )ethy 1) (methyl) amino )phenyl) -1 - (6- methyip yridin- 2- yl) -1 H-p yrazo le- 3 carboxyamide;
(107) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-(4-methylpiperazin-lyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(108) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-iV-(4-(4-acetylpiperazin-lyl)phenyl)-l-(6-methylpyridin-2-yl)-lH-pyrazole-3-carboxyamide;
(109) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-(( 1,1dioxido tetrahydro thiophen- 3 - yl) amino )pheny 1) -1 - (6- methyip yridin- 2- yl) -177-p yrazo le- 3 carboxyamide;
(110) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-acetamidophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(111) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4((dimethylamino)methyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
143
(112) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(2-(methylcarbamoyl)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(113) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(methylcarbamoyl)phenyl)-l(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(114) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-phenyl-
(115) 5-([l,2,4]triazolo[ 1,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-2V-(o-tolyl)-
(116) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(mtolyl) -1//-p yr azo le-3-carboxy amide;
(117) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(p-tolyl)177-p yr azo le-3-carboxy amide;
(118) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)- l-(6-methylpyridin-2-yl)-2V-(3(trifluoromethy l)phenyl) -177-p yr azo le-3-carboxy amide;
(119) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-l-(6-methylpyridin-2-yl)-iV-(4viny lpheny 1) -177-p yrazo le- 3 -carboxy amide;
(120) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-cyanophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(121) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-cyanophenyl)-1-(6methy lp yridin- 2- yI)-1 -/7- p yrazo le- 3 -carboxy amide;
(122) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-acetylphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(123) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-acetylphenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
144
(124) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(2-fluorophenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(125) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-fluorophenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(126) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-fluorophenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(127) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(128) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(129) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-chlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(130) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(131) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(132) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-bromophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(133) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,3-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
133 monocyclic or bicyclic heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from among N, O and S;
Re and R7 are each independently hydrogen, hydroxy, C1-6 alkyl, halo C1-6 alkyl or C3-6 cycloalkyl;
a and b are an integer of 0 to 4; and
(134) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,4-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(135) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2,5-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
145
(136) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-A^-(3,4-difluorophenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(137) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3,5-difluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(138) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-chloro-2-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(139) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-chloro-2-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(140) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-chloro-4-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(141) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3,4-dichlorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(142) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(2-bromo-4-fluorophenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(143) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-(methoxythio)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(144) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(methoxythio)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(145) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-(methylsulfmyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(146) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(methylsulfmyl)phenyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(147) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(methylsulfonyl)phenyl)-1-(6methylpyridin-2- yI)-1 /7- pyrazole-3-carboxyamide;
146
(148) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-sulfamoylphenyl)-l-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(149) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(4-(Smethylsulfonimidoyl)phenyl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(150) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(propylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(151) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-(propylsulfonyl)phenyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(152) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-iV-(6-fluoropyridin-3-yl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(153) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(6-chloropyridin-3-yl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
154 of Claim 1 to a subject in need of treatment of a carcinoma mediated by overexpression of
TGFp.
[Claim 131
The method of Claim 12, wherein the carcinoma is selected from the group consisting of carcinomas of lung, breast, liver, biliary, gastrointestinal tract, head and neck, pancreas, prostate and cervix, multiple myeloma, melanoma, glioma and glioblastoma. [Claim 14]
The pharmaceutical composition of Claim 5 or 6, which is for preventing or treating a fibrotic disease or a fibrotic condition.
[Claim 151
The pharmaceutical composition of Claim 14, wherein the fibrotic disease or the fibrotic condition includes one or more diseases selected from the group consisting of liver fibrosis, kidney fibrosis, pulmonary fibrosis, irritable pneumonia, interstitial fibrosis, systematic sclerodermie, macular degeneration, pancreas fibrosis, splenic fibrosis, cardiac fibrosis, species septic fibrosis, bone marrow fibrosis, vascular fibrosis, skin fibrosis, eye fibrosis, joint fibrosis, muscle fibrosis, thyroid fibrosis, endocardial myocardial fibrosis, peritoneal fibrosis, after peritoneal fibrosis, progressive congenital trophoblastic fibrosis, allogeneic systematic fibrosis, fibrosis complications of surgery and infection fibrosis. [Claim 161
The pharmaceutical composition of Claim 5 or 6, which is for preventing or treating a cancer or a tumor.
[Claim 17]
The pharmaceutical composition of Claim 16, wherein the cancer is selected from the group consisting of liver cancer, hepatocellular carcinoma, thyroid cancer, colorectal cancer, testicular cancer, bone cancer, oral cancer, basal cell carcinoma, ovarian cancer,
(154) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(6-methoxypyridin-3-yl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(155) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(2-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(156) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(3-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(157) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(4-fluorobenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(158) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(3-methoxybenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
(159) 5-([ 1,2,4]triazolo[l, 5-a]pyridin-6-yl)-2V-(4-methoxybenzyl)-1-(6methy lp yridin- 2- yl) -177-p yrazo le- 3 -carboxy amide;
147
(160) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-A^-(4-(dimethylamino)benzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(161) 5-([l ,2,4]triazolo [ 1,5-a]pyridin-6-yl)-2V-(-acetamidobenzyl)-1-(6methy lp yridin- 2- yl) -1 H-p yrazo le- 3 -carboxy amide;
(162) 5-([ 1,2,4]triazolo [ 1,5-a]pyridin-6-yl)-1 -(6-methylpyridin-2-yl)-2V-( 1 (methylsulfonyl)-1 A/-pyrazol-4-yl)-177-pyrazole-3-carboxyamide;
(163) 5-([l,2,4]triazolo[l,5-a]pyridin-6-yl)-2V-(l-cyclopropyl sulfonyl)-177pyrazol-4-yl)-l-(6-methylpyridin-2-yl)-177-pyrazole-3-carboxyamide;
(164) iV-(4-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(165) iV-(3-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(166) iV-(2-methoxyphenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(167) iV-(4-(2-methoxyethoxy)phenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)- 177-pyrazole-3-carboxyamide;
(168) 2V-(benzo[<7] [l,3]dioxo 1-5-yl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)-177-pyrazole-3-carboxyamide;
(169) 2V-(2,3-dihydrobenzo[£][l,4]dioxin-6-yl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
(170) iV-(4-(dimethylamino)phenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6yl)- 177-pyrazole-3-carboxyamide;
(171) l-(6-methylpyridin-2-yl)-iV-(4-morpholinophenyl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
148
(172) 2V-(4-(4-methylpiperazin-l-yl)phenyl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
(173) 2V-(4-(4-acetylpiperazin-l-yl)phenyl)-l-(6-methylpyridin-2-yl)-5(quinoxalin-6-yl)-177-pyrazole-3-carboxyamide;
(174) 2V-(4-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(175) 2V-(3-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177- pyrazole-3-carboxyamide;
(176) 2V-(2-cyanophenyl)-l-(6-methylpyridin-2-yl)-5-(quinoxalin-6-yl)-177pyrazole-3-carboxyamide;
(177) l-(6-methylpyridin-2-yl)-iV-(4-(morpholinomethyl)phenyl)-5-(quinoxalin-
155 brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, colorectal cancer, vesical carcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, lung cancer, skin cancer and other solid cancers.
[Claim 181
The pharmaceutical composition of Claim 6 or 7, which is for preventing or treating a disease selected from the group consisting of kidney-, liver- or lung-fibrosis, glomerulonephritis, diabetic renal disease, erythematous nephritis, hypertension-induced renal disease, kidney interstitial fibrosis, kidney fibrosis derived from drug exposure complications, HIV-related renal disease, organ transplantation gangrene, liver fibrosis caused by all diseases, hepatic dysfunction caused by infection, alcohol-induced hepatitis, biliary disorder, pulmonary fibrosis, acute lung injury, adult respiratory pain syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary fibrosis caused by infection or toxic factors, cardiac fibrosis after myocardial infarction, congestive heart failure, dilated cardiomyopathy, myocarditis, vascular stenosis, restenosis, atherosclerosis, visual impairment, corneal injury, proliferative vitreoretinopathy, excessive or exacerbated scar or keloid formation in the dermis occurring during wound healing from trauma or surgical wounds, peritoneum and subcutaneous adhesion, skin sclerosis, fibrosclerosis, progressive systemic sclerosis, dermatomyositis, multiple myositis, arthritis, osteoporosis, ulcer, impaired nerve function, male impotence, Alzheimer’s disease, Raynaud’s disease, fibrous cancer, metastasis growth of tumors, radiation-induced fibrosis and thrombosis.
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